Stanislas Wawrinka seriously dented his hopes of reaching the ATP season final when crashing out of the Swiss Indoors with a 6-4, 6-3 first-round loss to Edouard Roger-Vasselin on Tuesday.
The same fate befell second seed Tomas Berdych when the next man in the queue to qualify for the eight-man year-end event was beaten by Ivo Karlovic 4-6, 7-6 (7/4), 7-6 (7/2).
Berdych had a chance to serve out a three-set win but failed and then could not extricate himself from the big-serve danger of the Croatian, who won with 23 aces in almost two and a half hours.
Wawrinka, now five times a loser in Basel opening matches, ended disappointingly on a fifth double-fault of an evening to forget for the fourth seed at his home event.
The Swiss stands provisionally eighth in the race to the World Tour Finals, but he now must work a miracle next week at the Paris Masters - the last event of the regular season - to save his qualifying hopes.
The US Open semi-finalist, who put out holder Andy Murray in New York and reached a September semi-final in Kuala Lumpur, showed only a shadow of his game as he went down to the Frenchman in 71 minutes.
After dropping the first set, the sluggish Swiss was broken to start the second and could never close the gap on his 65th-ranked opponent.
Meanwhile, Uzbek Denis Istomin booked a second-round meeting with former world number one Roger Federer as he beat Argentina's Horacio Zeballos 7-5, 7-6 (7/3).
Federer, whose poor form this season has yielded just one title and seen him slump to sixth in the world, is battling to reach the eight-man World Tour Finals in early November, with every win here and in Paris crucial to him appearing in a tournament he has won six times.
He began with a victory in front of his home crowd on Monday as he beat Frenchman Adrian Mannarino.
Federer has never lost to 48th-ranked Istomin in five previous meetings, defeating him most recently at Indian Wells in March despite suffering from a painful back.
Japanese sixth seed Kei Nishikori, losing finalist two years ago to Federer, reached the second round by winning 6-2, 6-4 against Switzerland's Marco Chiudinelli, a wild-card entry and childhood friend of Federer.
Nishikori next plays Croatian Ivan Dodig, who advanced in just nine minutes as Argentine Carlos Berlocq retired while trailing 2-0.
"The second set was tougher for me," said Nishikori. "He started playing a lot better, coming to the net and being aggressive. It looked like he could take it into a third set. But I'm glad I was able to win in two."
Marcos Baghdatis also reached the second round, winning his first match since late September with a defeat of German qualifier Benjamin Becker 7-6 (10/8), 6-1.
The Cypriot will face the winner from top-seed and title-holder Juan Martin del Potro and Swiss wild card Henri Laaksonen.