Garbine Muguruza retired from her first-round match against Barbora Strycova due to a virus, while Angelique Kerber and Sloane Stephens made early China Open exits on Monday.
Top seed Muguruza was clearly not at her best as she lost the first set 6-1 and Strycova had won the first two games of the second before the world number one decided she could not continue.
Kerber's hopes of claiming a first title of a miserable year were ended by Alize Cornet, the Frenchwoman prevailing 6-4 6-4 to reach the third round.
Stephens has not won a match since sensationally claiming the US Open title on home soil and went down 6-3 6-0 to compatriot Christina McHale following a rain delay.
Dominika Cibulkova was another seed to fall at the first hurdle, squandering a 5-0 lead in the first set as Elise Mertens fought back to win 7-6 (7-4) 6-1.
Caroline Wozniacki responded to her second-round loss at the Wuhan Open last week with a straight-sets success over Anastasia Pavlyuchenkova in a repeat of the Pan Pacific Open final, which the Dane won last month.
CoCo Vandeweghe, Peng Shuai, Varvara Lepchenko and Elena Vesnina all made it through to the second round.
WUHAN VIRUS ACCOUNTS FOR TOP SEED
Muguruza missed out on a first title since moving to the top of the rankings in Wuhan and the Wimbledon champion will not claim a third tournament win of the year in Beijing.
The 2015 China Open winner said: "It's very tough, I got a virus in Wuhan I couldn't perform today.
"It's the easy way to think: 'I don't go on the court'. I want to feel like giving the last chance, going on the court, just hit a few balls, see how I'm going to feel, try to turn things around.
"I don't want to retire before the tournament starts."
ANOTHER SETBACK FOR KERBER
Kerber has slipped from the top of the rankings to 12th in what has been very much a season to forget after hitting new heights in 2016.
Cornet became the latest player to take advantage of the German's struggles, coming from 3-1 down in the opening set and winning the second despite twice being a break down.
Kerber lost to eventual champion Caroline Garcia in the first round in Wuhan and fell to another French Opponent a week later. Cornet will now take on Garcia in round three.
'THERE'S NOT MUCH TO SAY ABOUT' - STEPHENS NOT DWELLING ON MCHALE LOSS
Stephens suffered a shock loss to Wang Qiang in her first tournament since defying the odds to claim a first major but has not win since hammering Madison Keys in the final at at Flushing Meadows.
She was no match for McHale, who dumped the 15th seed out in only 65 minutes after winning the last seven games of the match.
Stephens said: "It was just a tough day. There's not much to say about it. It was obviously not a great match, so I just want to forget about it, move on, and try to have a better level for the next tournament."