Uphoff was last seen in Rising City, Nebraska on October 24, 1965. He and his wife took their four young children to Shelby, Nebraska and spent the day there before returning to their home in Rising City. At 11:30 p.m. that evening, Uphoff told his wife he was returning to Shelby for a beer. He drove away in his blue and white 1954 Oldsmobile Club Coupe 88 with Nebraska license plates numbered 25-B2602 and has never been heard from again. His vehicle was never found.

Uphoff was apparently having an affair with a local woman, Jacquelyn Rains-Kracman, in 1965. He was her husband's boss. Rains-Kracman's husband went so far as to tell Uphoff's wife about the affair, although Uphoff denied the relationship existed. Rains-Kracman disappeared a month before Uphoff did and has never been heard from again.

Authorities and both families believe Rains-Kracman and Uphoff ran away together. Members of both families believe the missing couple tried to contact them in the years after 1965. In 1967, a man called Uphoff's old house and asked to speak to his wife. The caller hung up when he was told Uphoff's wife no longer lived there. That same day, someone tried to call one of Uphoff's other family members through a pay phone but they were unable to speak to one another. It has not been confirmed that either caller was Uphoff, however.

Uphoff was declared legally dead in 1972. His and Rains-Kracman's families are continuing to search for them. Their cases remain unsolved.