The story begins in the mountains of Bavaria, Germany, where wildlife documentarian Ernest Helms (Michael Winters) is filming local wildlife. While filming, he discovers a man attempting to break into his rental car. After foiling the man's attempt, Helms prepares to drive away but is thwarted by the man smashing the driver's window. Helms, however, succeeds in escaping the crazed man, but receives a minor cut on his hand.
A few days later, in Frankfurt, Captain James Holland (Richard Dean Anderson), amidst preparations for his forthcoming transatlantic flight as Captain of Quantum Airlines Flight 66, is told by his doctor he does not have cancer. On board Flight 66, a Boeing 747, Helms (already displaying signs of illness) is assisted to his seat by flight attendant Brenda Hopkins (Kate Hodge). Shortly after takeoff, Helms rises from his seat and falls into cardiac arrest, and Brenda gives him CPR. Head flight attendant Barb Rollins (Jennifer Savidge) notifies Holland of the emergency, and the Captain and his check pilot, Daniel Robb (Richard Lawson) set a course for London's Heathrow Airport,. However they are turned away when British Air-Traffic Control informs them that one of the passengers (Helms) could be infected with a deadly strain of influenza.
Several harrowing events follow. The U.S. President (Edward Herrmann) unsuccessfully tries to sneak Flight 66 into RAF Mildenhall, disguised as a United States Air Force fighter plane and guided in by another, despite a recommendation otherwise by Ambassador Lee Lancaster (Robert Guillaume), but the British forces at the base jam the runway with emergency vehicles. Holland threatens to land anyway, only to pull up at the last minute, showing the U.S. Government how desperate the situation is. Soon thereafter, an investigation is set in motion by the Central Intelligence Agency. Flight 66 lands at the U.S. air base in Iceland, but one passenger is so distraught at being separated from her child and at being in quarantine that she runs down the airplane stairs and is shot and killed by U.S. troops in MOPP gear. Holland flies the aircraft toward Mauritania, but a female intelligence agent warns Holland that an assassin is trying to destroy the flight. Holland tricks the assassin (in a missile-armed Lear jet) into crashing and lands on Ascension Island.
The book mentions that the virus becomes less lethal and enters the human population. The movie indicates that the flight attendant who gave Helms CPR died six months after the incident, presumably from the virus.