It was a misery for the fourth seed in Shanghai, who was in need of a morale-boosting victory after his last outing resulted in a first round exit at the Japan Open to 103-ranked Tatsuma Ito.
The Australian Open champion, ranked world number four, started brightly in Shanghai, taking the first set in his tightly-fought battle with Gilles Simon of France.
But his 29th ranked opponent fought back aggressively to stay in the match and force a decider.
The Swiss 29-year-old broke serve at his first attempt in the final set with a ferocious smash shot.
He then appeared to be cruising, pounding his chest with his fist as he entered the third game, which he won after saving two break points.
Simon, a former world number six, broke back at his next attempt and then forced his way to 3-3 in a marathon ten-minute game.
Wawrinka appeared to cave in three games later, meekly surrendering his serve without scoring a point before Simon marched to a 5-7, 7-5, 6-4 victory.
The result could undermine Wawrinka's bid to confirm his place at the end of season ATP World Tour Finals, which involves the world's top eight players.
He is in fourth position in the Race to London but is desperately chasing points as he vies to hold off a closing pack who are all competing in Shanghai.
Only five berths remain for the London tournament, as Novak Djokovic, Rafael Nadal and Roger Federer have already qualified.
The fifth seed in Shanghai, David Ferrer, also faced a tough battle in his opening match, but finally overcame Slovak Martin Klizan 4-6, 7-6 (7/4), 6-4.
Klizan dumped Rafael Nadal out of the China Open at the quarter final stage last week, but could not repeat his heroics against his Spanish opponent at the Masters 1000 event.
Meanwhile, tenth seed Grigor Dimitrov of Bulgaria lost to Julien Benneteau of France 7-5, 6-3.