An ailing Rafael Nadal added his name to the list of upsets at the Shanghai Masters after the Spaniard suffered a 6-3, 7-6(6) loss to Feliciano Lopez in Wednesday's second round, as fourth seed Stanislas Wawrinka and in-form Kei Nishikori also made early exits.
Nadal's great rival Roger Federer survived a huge scare, saving five match-points before overcoming Argentina's Leonardo Mayer 7-5, 3-6, 7-6(7).
World number one Novak Djokovic kicked off his title defence with a 6-3, 6-4 win over Dominic Thiem, while Andy Murray did his hopes of grabbing a spot at the season-ending ATP World Tour Finals no harm with a 7-5, 6-2 win over Jerzy Janowicz.
Nadal has been diagnosed with appendicitis which will require surgery and while the world number two tried to play through the pain he was clearly not at his best.
"For sure (I don't feel) perfect," said Nadal. "It's the same way that I felt before. A little bit more dizzy now. But that's it. Nothing that I have to worry about. When you lose a match, it is not the moment to talk about obvious things. I lost. Feli played better than me."
Nadal said he had plans to have the surgery to remove his appendix at the end of the year.
With five spots still up for grabs at the season-ender in London, Australian Open champion Wawrinka, who fell at the first hurdle in Tokyo last week, suffered the same fate in China with a 5-7, 7-5, 6-4 defeat to Frenchman Gilles Simon.
"Two weeks I didn't win matches," the Swiss said on the ATP's official website. "But you have to accept that and see what was the problem. I don't think I lost my game. I think I'm playing okay. I just had two really bad matches."
American Jack Sock produced another upset when he defeated Japan's Nishikori 7-6(5), 6-4.
It was the American's first win over a top 10 opponent and brought Nishikori's hot streak to an end. The Japanese came into the tournament after wins in Kuala Lumpur and Tokyo.
Federer had to dig deep to avoid a similar fate against an inspired Mayer.
The Swiss master saved two match points to make it 5-5 in the decider and rallied from 4-1 down in the tiebreak to seal the victory.
Djokovic, who is undefeated in 26 matches in China, had too much class for up-and-coming Austrian Thiem.
"I had to be on alert from the start because he was serving already 215 kilometers per hour in the first service game," said Djokovic. "He was serving big, playing big."
Briton Murray made short work of an out-of-touch Janowicz and will next meet David Ferrer after the Spaniard survived a tense encounter against Martin Klizan.
The fifth seed found the going difficult against his Slovak opponent before grinding out a 4-6, 7-6(4) 6-4 victory as he looks to climb up from his current 10th position in the race for the Tour Finals.