Molinari leads Dubai Desert Classic as McIlroy struggles
Former British Open champion Molinari, now 418th in the world rankings, made eight birdies in a seven-under par 65.
The 43-year-old Italian is two shots clear of Sweden's Mikael Lindberg, with Swiss player Joel Girrbach and South African JC Ritchie a stroke further back.
It was Molinari's lowest round on the European Tour since January 2024.
"It's been a long time. I've changed everything and then I've changed back," said the 2018 Ryder Cup winner, who has not won a professional title since the Arnold Palmer Invitational seven years ago.
"Not super unexpected but I wasn't expecting a score like that. Last week I felt very rusty, so I was hoping it would be very good prep for this week."
Molinari will have plenty of work to do to hang onto his lead with a host of top players in the field this week.
Shane Lowry and defending champion Tyrrell Hatton, who played starring roles in Europe's Ryder Cup triumph at Bethpage Black last year, both made solid starts with two-under rounds of 70.
"Standing here right now, I'm very happy with that score," said England's Hatton after his first competitive round of the year.
"It was pretty tough this morning. Feel like I hit some pretty scruffy golf shots, which in some ways is to be expected."
It was a disappointing day though for McIlroy, who hit his approach shot on the par-five 18th hole into the water en route to a closing double-bogey.
The Masters champion had earlier mixed three birdies with two bogeys.
McIlroy will need to make a move on Friday to get into contention for a fifth title in the event, as will world number three Tommy Fleetwood who also carded a one-over 73.