The Swiss three-time Grand Slam winner was beaten 7-6 (7/4), 6-3 in the first round by outsider Damir Dzumhur.
Wawrinka was playing for the first time since suffering a right knee injury at the Australian Open a month ago, where he reached his eighth major semifinal before falling to Roger Federer.
And following defeat by the 77th-ranked journeyman from Bosnia-Herzegovina, he admitted that his fitness was lacking after only a week of practice.
"I started well but it was tough because I was missing a little bit something. In practice it was starting to be OK the last few days, but today I was missing something."
Dzumhur made the most of his Dubai debut to advance into a match with Marcel Granollers of Spain. The loss was the third from ten matches this season for Wawrinka.
After taking an early lead, Wawrinka found his game slipping. By the time he got the the first-set tiebreak, he was playing catch-up.
The second seed was broken twice for 5-1 in the second set before a brief rally in which he broke back once.
Despite his exit, Wawrinka said that his knee was giving him no pain, a positive sign heading into back-to-back Masters 1000 events starting next week in Indian Wells and Miami.
"I need to focus on myself. I need to practise more, to get in (a) better level to expect to do some good results," Wawrinka said.
"I'm quite unhappy to lose first round. It's tough, because I played well last year here. I was happy to be back. I was happy to be back on the ATP Tour after a month.
"I was excited and I wanted to do better this week. But the result is not there, but I think in general it's positive for my tennis."
Elsewhere in the first round, Evgeny Donskoy beat fellow Russian Mikhail Youzhny 6-4, 6-4 to set up a match with Federer.
Spain's Fernando Verdasco defeated Andreas Seppi of Italy 6-2, 7-5.