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FBI agent Stafford arrives in Spain to apprehend a convicted murderer, American Brett Matoon, who escaped from prison two years earlier. Unaware that the authorities know of his whereabouts, Brett proceeds with his plans to marry his girl friend, American showgirl Jean Gurney. Meanwhile, Lord Robert Leverett, deeply disturbed by the recent death of his young daughter Lori, illegally purchases a powerful chemical poison and after murdering the courier, proceeds with plans to take the chemical onboard an international flight to New York City. The next day, Stafford and Spanish police captain Rivas arrest Brett, who is allowed to telephone Jean to bid her farewell. Bewildered by Brett's abrupt call, Jean hastens to his apartment where she learns from the manager that Brett has been escorted to the airport. Jean follows and finds Brett and Stafford waiting for El Conquistador flight 400 to New York. Rivas informs Stafford of each passenger's identity as they board, including eccentric spinster Miss Hooten, famous opera singer Madame Galli-Cazetti, the Reverend Dean Halltree, Mrs. Lanyard and her young daughter Laura and Leverett and his wife Ursula. Upon seeing Brett board the plane with Stafford, Jean impulsively purchases a ticket. Shortly after takeoff, Miss Hooten notices that Brett is handcuffed to Stafford and spreads the information among the passengers. When Jean approaches Brett and reacts to the handcuffs, Stafford allows Brett to meet with her privately in the lounge, where he explains his situation: After the Korean war, aviation hero Brett struggles to find work. Stopping at a local bar one night, Brett is the only customer present when two men arrive and, angered over the owner's refusal to purchase liquor from their organization, shoot him and the busboy and, after knocking out Brett, place the gun in his hand. With no other witnesses to the crime, Brett is convicted for both murders and is convinced he will never be proved innocent. Meanwhile in the present, while Jean vows to stand by Brett, in the luggage compartment, the chemical mix in Leverett's trunk has become active. Unaware that Miss Hooten has eavesdropped on Brett and Jean's conversation, then repeated it in the main cabin, the couple is surprised when Stafford joins them and asks Brett if he still has the Spanish wedding license. Although Brett protests that Jean should not marry a felon, she is delighted by the suggestion and Halltree marries the couple with several passengers as witnesses. At the urging of Miss Hooten, Mme. Galli-Cazetti grudgingly agrees to give up her exclusive state room to the couple as a wedding gift. Later, Leverett notices young Laura sitting nearby and points out her likeness to their daughter to Ursula. In the cockpit, the pilot grows drowsy from the whiffs of gas coming from the luggage compartment below and turns the flight over to the co-pilot, retiring to his bunk to rest. As night falls and the passengers retire, the chemical in the trunk catches fire, releasing more powerful poisonous fumes. Upon getting a glass of water for Jean, Brett spots one of Stafford's associates asleep and steals his pistol. Jean has seen the theft and when she asks Brett his plans, he reveals his intention to hijack the plane to Canada where he can escape. Jean then reluctantly agrees to help. The growing fire in the luggage compartment sets off the automatic sprinklers and alerts the crew in the cockpit to the emergency. In the main cabin, the increasing heat has unnerved several passengers and when the co-pilot announces a fire, several panic. Leverett asks Mrs. Lanyard if he might comfort Laura as the flight attendants struggle to calm the passengers. Although the fire is extinguished, the chemical continues reacting, creating an oozing foam substance that radiates more noxious fumes. After detecting the gas in the cockpit, the co-pilot discovers the pilot and navigator have both died and radios a report ahead to the New York airport. Just after announcing to the passengers that they must make an emergency landing on water, the co-pilot collapses and dies. As the passengers again grow distraught, Leverett, unnoticed, destroys the radio transmitter. Curious about the emergency, Brett goes to the cockpit where he discovers the dead crew and, with Stafford, goes down into the luggage compartment. Discovering the gaseous substance coming from the trunk, Brett attempts to destroy it as Leverett appears and takes claim for the poisoning. When Brett ignores Leverett's warning to leave the trunk alone, Leverett brandishes a gun and fires, but Brett pulls out his pistol and kills him. Stafford praises Brett, but insists on taking the pistol. Back in the cockpit, Stafford orders Brett to take over flying the plane, which has been on automatic pilot. In order to provide fresh air to the passengers, Brett brings the plane down several thousand feet so that numerous windows can be broken without danger of decompression. Jean joins Brett in the cockpit and as they struggle to contact the airport by radio, Brett discovers the broken transmitter. Brett then admits to Jean that he cannot hijack the plane with so many gravely ill passengers. In the main cabin, meanwhile, despite the attempts to clear the fumes, a few passengers are stricken and die. Brett maintains the course taken by the automatic pilot and soon sees lights ahead, indicating land. A little later, the airport lights come into view and despite his inability to contact the tower for clearance, Brett lands the plane, which is quickly surrounded by police, firefighters and ambulances. Brett tells Jean he must make an escape attempt, but when he does, Stafford shoots and wounds him. As the surviving passengers deplane and are welcomed by their families, bureau agents, escorting a recently arrested suspect in Brett's case, meet Stafford. When the man identifies Brett as the "patsy" framed for the bar murders, Stafford assures Brett and Jean that Brett will soon be a free man.