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At a bus stop café along a Southern Californian road, independent bus driver Johnny Chicoy readies his rickety old bus "Sweetheart" for the fifty-mile run to the mission in San Juan, Mexico. Before leaving, the darkly handsome Johnny quarrels with his tempestuous wife Alice about her drinking and lust for money. Soon after, the passengers arrive to begin their journey: Camille Oakes, a sweet blonde stripper on her way to a job in San Juan; Ernest Horton, a wisecracking traveling salesman; Van Brunt, a crotchety demanding old man in a hurry to reach San Juan; and Elliott and Bernice Pritchard and their rebellious teenage daughter Mildred. The bickering Pritchards are taking Mildred on the trip in hopes of breaking up her relationship with a boy back home. Joining them are bus stop employees Ed "Pimples" Carson, the young handyman and mechanic, and Norma, the star-struck waitress who dreams of being discovered in Hollywood. As a bulletin comes over the radio warning of an approaching storm, Camille pages through a girlie magazine and discovers that she has been slandered by an exposé. Disregarding the warning, the bus starts on its way, and Johnny, still angry at Alice, leaves her behind. As it starts to rain, the man-hungry Mildred begins to flirt with Johnny while Ernest amuses Camille by displaying the novelties he sells. The bus winds down the slick mountain roads until a massive landslide rumbles down the hillside, blocking the road and shaking up the passengers. When a highway patrol helicopter lands to inform Johnny that the main road to San Juan is closed, Johnny phones Alice to apologize, but when she answers, drunk and abusive, he decides to navigate the bus over the old road to San Juan and then leave Alice for good. As the bus embarks upon its bone-jolting ride, Pritchard spots the article about Camille and leers at her. Ernest, smitten by the alluring Camille and blissfully unaware of her profession, is kind to her and she basks in his benevolence. Seeing that the wobbly old bridge that spans the river is threatened by onrushing rapids, Johnny insists the passengers walk across. Once they are safely on the other side, Johnny guns the bus's engine, but midway across, a tree, swept by the violent current, smashes into the bridge, causing it to break in two. When the bus's wheels skid, Carson hurries to help free them, and Johnny safely reaches dry land. Meanwhile, at the café, the helicopter pilot, bent on taking advantage of Alice's unhappiness, makes romantic advances to her, but she rebuffs him. Chagrined, the pilot then offers to fly Alice to meet Johnny in San Juan. While lurching down a hill, the bus's water-soaked brakes fail, sending it crashing into a mud hole. While the passengers bicker and complain, Johnny goes to look for a farmer with a tractor who can extract the bus from the mud. When Johnny discovers that the nearest farmer will not return home until later that afternoon, he takes refuge in the barn from the teeming rain. Mildred, restless, follows and seduces him in the hay. Back at the bus, Pritchard observes to his wife that they are responsible for their daughter's maladjusted behavior. Once the rain stops, Camille and Ernest stroll through the fields and Ernest proposes. Later, Pritchard compliments Ernest for his conquest of Camille and shows him the exposé. Shocked, Ernest returns to the bus and wordlessly moves away from Camille. When the farmer finally returns, Johnny enlists his help, and on his trek back to the bus, realizes that he is still in love with Alice. Soon after, Alice arrives, and upon learning that Johnny has spent the afternoon with Mildred, is deeply hurt but nevertheless boards the bus to complete the journey to San Juan. Once there, Alice informs Johnny that she is leaving him and walks away. Camille is met at the station by the man who has hired her to strip, but when Ernest asks her to return to Los Angeles with him, she informs the man she is permanently retiring. Mildred, meanwhile, proceeds to the telegraph counter and wires her boyfriend that she is coming home to marry him. When Johnny learns that Alice has boarded the bus bound for Reno, he jumps in Sweetheart and follows her, and as the highway lights illuminate the bus's darkened interior, he sees Alice seated in the back. They then drive home together.