Ronnie O’Sullivan lost 4-1 to world number 63 Alexander Ursenbacher in the first round of the British Open.
The seven-time world champion’s error-strewn display saw him lose for a third time against the Swiss player, 26.
Shaun Murphy also lost when he went in-off after potting the black in a final-frame decider against Gary Wilson.
Last year’s winner Mark Williams and former world champions Judd Trump and Mark Selby made it through in Milton Keynes.
O’Sullivan, 46, has won only once in three previous meetings with Ursenbacher and found the Swiss in fine form.
The reigning world champion fell 2-0 behind and, despite pulling one frame back, missed a number of simple pots which his young opponent seized on to set up a second-round meeting with England’s Joe O’Connor.
Murphy, the 2005 world champion, suffered a stroke of misfortune to lose 4-3 against last year’s runner-up Wilson.
Both men made centuries, Murphy running in 112 in the third frame after missing the 15th red when on target for a 147, while Wilson levelled with a 137 to set up a deciding frame.
Murphy came back from 49-12 down in the decider to go 51-49 in front after rolling in the pink but sank the white after potting the final black to lose the match.
World number 33 Wilson said: “I was the most surprised out of anybody, because I was sitting in my chair thinking I had lost. Shaun’s a lovely bloke and took it in great spirits.”
Wales’ Williams kicked off the defence of his title with a 4-1 victory over Estonia’s European amateur champion Andres Petrov.
Selby beat world number 16 Ricky Walden and world number two Trump overcame China’s Si Jiahui by the same scoreline.
Scotland’s John Higgins, Northern Ireland’s Mark Allen, China’s Zhao Xintong and English trio Kyren Wilson, Jack Lisowski and Stuart Bingham were also among the top-16 players to make it safely through on the first day of play.
Barry Hawkins, ranked ninth in the world, added his name to that list after squeezing past Duane Jones 4-3 in the final first-round match, but Belgium’s world number 10 Luca Brecel lost 4-1 to 2006 world champion Graeme Dott.