Three terrorists who break into a bacterial research laboratory at the International Health Organization in Geneva, Switzerland, are contaminated with pneumonic plague bacteria during a shootout with American guards. One is killed and one wounded, but the third man escapes. At the train station he sneaks aboard the Geneva-Stockholm Express and hides in the mail car. Col. Mackenzie from U.S. Army staff headquarters in Munich, West Germany, arrives at the medical center to take charge of the investigation. Dr. Elena Stradner has isolated the wounded terrorist, who is already showing the effects of pneumonic plague, but he dies before Mackenzie can get any information from him. Mackenzie orders the body burned immediately. Dr. Stradner demands to become an equal partner in the unfolding drama because, as she reminds Mackenzie, the Americans were working secretly on plague bacteria on foreign soil in violation of United Nations regulations. When army doctors find a Swedish peace group booklet and a Geneva-Stockholm Express ticket among the dead men’s possessions, Mackenzie attempts to contact the train, but nobody aboard is manning the radio. There are a thousand people on the train, and Mckenzie knows that if the terrorist is moving among them, many may have already been infected. Furthermore, no Western European country would allow Mackenzie to stop the train within its borders. His only alternative is to prevent anyone from getting on or off and divert it from the next stop, Basel, Switzerland. Aboard the express, in the first-class section and dining car, are Jennifer Rispoli, a successful novelist; her ex-husband, neurosurgeon Jonathan Chamberlain; Nicole Dressler, the wife of a wealthy German arms manufacturer; her young boyfriend, mountaineer Robby Navarro; a black priest named Haley; Susan and Tom, a young American couple; Mrs. Chadwick and her young daughter; and the conductor, Max. Nearby is Max’s old friend, an amiable watch peddler named Herman Kaplan, who tries to wheedle his way into first-class. The terrorist is still hiding in the empty mail car, where the train radio is located, but the plague has made him ravenously thirsty. After drinking from the water bowl of Mrs. Dressler’s caged basset hound, the terrorist, now visibly sick, slips out among the passengers. Jonathan sees him in the dining car kitchen and asks if he’s all right. Back in Geneva, Mackenzie tells U.S. Army headquarters that his only solution is to isolate the train in Nuremberg, West Germany, and move it into Poland, where there’s a rail line near Janov, just beyond a bridge called the Cassandra Crossing, that hasn’t been used in years. The area would be a good place to quarantine the passengers. When a list of the passengers comes through on the computer, Dr. Stradner recognizes Jonathan’s name and tells Mackenzie he’s a famous neurosurgeon. Meanwhile aboard the express, Jennifer sees a sign pointing the wrong way and alerts Jonathan that the train is going in the wrong direction. At that moment, Max comes by to tell Jonathan he has a call. Both Jonathan and Jennifer follow Max to the radio in the mailroom. When Mackenzie tells Jonathan that a plague carrier is aboard the train, the doctor says that he saw the man an hour earlier. Jonathan and several others, including Max, search the train until they return to the mail car and find the terrorist among the mailbags. Herman, who speaks a little Swedish, tries to talk to him, but the Swede sinks into unconsciousness. A few feet away, the basset hound also looks sick. Mackenzie tells Jonathan that a helicopter flying above the train will retrieve them. The helicopter drops a basket outside the mail car’s open door and hauls up the dog, but before the passengers can get the Swede into the basket, the train enters a series of tunnels through an increasingly mountainous area, forcing the helicopter to abandon the effort and rush the dog back to Geneva. Mackenzie and Dr. Stradner tell Jonathan that since the plague has a sixty-percent kill rate and no antidote, the train is heading for a quarantine area in Poland. When Jonathan demands a medical team, Mackenzie says help will be available when the train stops at Nuremberg. Many passengers are already showing early signs of plague, so Max, Jennifer and Jonathan move the sickest to a car near the end of the train. As the train pulls onto an isolated track near Nuremberg, armed American military police surround it and threaten to kill anyone who tries to escape. Wearing white hazardous-material suits and oxygen masks, the soldiers seal all the windows with steel barriers and bring aboard medicines and a medical team. Several bodies, including the terrorist’s, are removed in metal containers. The soldiers also aerate the train with oxygen and collect all the matches and cigarette lighters, except Herman’s. When Herman finds out that the train’s destination is Janov, where the Nazis exterminated his family during World War II, he becomes hysterical. Jonathan calms him with a sedative. By now, Jennifer, twice divorced from Jonathan, realizes she is falling in love with him again. In Geneva, Dr. Stradner, observing the dog in a special isolation room, tells Mckenzie that it is still alive, even improving, but Mackenzie is more concerned with reports about the bridge at Cassandra Crossing. On the train, Max tells Jennifer that the Cassandra Crossing bridge is dangerous and nobody uses it anymore. Herman adds that the people who lived below the bridge moved away after the war. He also admits that he’s ready to return to Janov now, because it is God’s will that he rejoin the ghosts of his family there. When Jonathan relays the information that the bridge is unsafe, Mckenzie assures him that it has been repaired and tested, but the doctor knows he’s lying. He tells the other passengers it is time for action. Father Haley reveals himself to be an agent who is tracking Robby as a drug trafficker, but Robby knocks him out and grabs his gun. Taking Mrs. Dressler to the mail car, Robby disarms one of the guards, grabs his machine gun, shoots out the radio and demands the train be stopped. Jonathan convinces him to lay down the gun because there are too many armed guards on the train. At that point, Tom brings Susan into the car to show Jonathan that her plague symptoms have disappeared. Other passengers who were sick are also well again. In Geneva, Dr. Stradner notices the same thing with the basset hound. She realizes the enriched oxygen in the lab—and on the train—is over-stimulating the plague bacillus and burning it out. As long as the passengers weren’t infected through an open wound, the oxygen should cure them, but with the train radio shot to pieces she cannot contact Jonathan. In any event, Col. Mackenzie tells her he won’t stop the train until it gets to Janov. She accuses him of putting a thousand innocent lives at stake, but nothing can change Mckenzie’s plans. Simultaneously, the commanding soldier on the train refuses to listen to Jonathan and has him removed from the mail car, which is now the train’s command center. Jonathan and several passengers capture some guards and take their weapons. Robby, with his mountaineer training, climbs outside the speeding train and crawls along the side to get to the locomotive, but a soldier shoots him. Jonathan moves the first-class passengers into the rear car. As a gun battle rages in the narrow corridors of the cars, several soldiers and passengers are killed. Tom is wounded. Jonathan decides to explode a propane canister in the dining car, but he only has one match for Jennifer’s homemade fuse, and the fuse fizzles out. Before the soldiers can overtake them, Herman walks into the propane-filled dining car with his lighter and sacrifices himself. The car’s destruction gives Jonathan access to the coupling mechanism, and he separates the rear cars just as the rest of the train begins crossing the long bridge. The weight of the locomotive and its cars is too much; the bridge gives way and hundreds of passengers fall to their death below. In Geneva, Mackenzie tells Elena Stradner that his job was to contain not only the disease but the very idea of the disease, which meant everything had to be destroyed and the passengers sacrificed. Mackenzie assures her that the oxygen that saved the infected passengers would have burned everything on the train when it crashed. As Jonathan and Jennifer embrace, a couple of hundred survivors leave the separated cars at the end of the Cassandra Crossing bridge, but Mackenzie calls his superiors to report a tragic accident with no survivors, and “on that you have my personal assurance.” The colonel hangs up, puts on his coat and leaves.