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Four-time major winner McIlroy, who would complete the career Grand Slam by winning next month's Masters, finished 54 holes on eight-under 208.
Only Matthew Fitzpatrick was on the course at Bay Hill in Orlando ahead of the 29-year-old Northern Ireland star, the Englishman on nine-under.
"It's so bunched," McIlroy said. "I'd still say the 2- and 3-unders still have a chance to win the tournament."
McIlroy birdied four of the first six holes and three of the last our holes while taking his lone bogey at the par-4 eighth.
"I've just been trying to play high cuts into every single pin I can look at. It's the only way I feel like I can stop the ball near the pin," McIlroy said.
"I knew the key for me today was to hit fairways. The greens are so pure. Whenever you start them on line they have a good chance."
McIlroy put his approach to five feet and made birdie at the par-3 second then sank an 11-foot birdie putt at the par-4 third.
After a three-putt par at the par-5 fifth, McIlroy sank a 26-foot birdie putt at the fifth and then blasted from a greenside bunker inches from the cup on the way to a birdie at the par-5 sixth.
He escaped nine with a par after "probably the worst mud ball I've ever had... it was good to get away with a four there."
McIlroy's ferocious finish saw him sink short tap-in birdies at 15 and the par-5 16th then sink a nine-foot par putt at the par-3 17th and drop a birdie putt from the same distance at 18.
"It was nice for that one to go in to cap off a really good round," McIlroy said.
McIlroy has not won since taking last year's crown at Bay Hill, his 14th career PGA victory.
"This golf course has played much tougher from the beginning compared to previous years," McIlroy said. "The course is going to get tougher as it goes along.
"The greens are getting so firm and so fast out there, anything above the hole you're going to have trouble getting it to stop."
McIlroy won major titles at the 2011 US Open, the 2012 and 2014 PGA Championship and the 2014 British Open.
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