Harrington made two tough par putts early, then a bunch more for birdies on his way to a 6-under 66, giving him a one-shot lead over Vijay Singh and Jason Bohn on a day of ever-changing wind that kept everyone on their toes.
'One mis-hit over here, it can cost you,' Singh said.
Tiger Woods found that out on the 18th hole as he tried to stay in range of the leaders. He changed clubs when he felt the wind shift and still flew the green to take bogey and an opening round of 70.
'It was an 8 (iron) when the wind was off the right, then it became a 7 when the wind was in, then the wind went in off the left, then went down off the left, and when I hit it was down off the right, when I thought it was in off the right,' he said. 'There you go.'
And there it went.
The scoring was decent and the leaderboard eclectic, about the only common thread was that it favored those with health issues.
During his three-week break after the Masters, Harrington had an early stage of skin cancer removed from his forehead and put his clubs down for a week, which is about as unusual as him taking a break.
Trevor Immelman lost 22 pounds from a parasite he picked up during the Masters and still isn't at full strength, although he managed a 68.
David Berganio Jr. went for a hike in the hills near his home in California and injured his back, but he shot 69.
About the only thing that mattered was trying to get through the fast, tree-lined course without getting into too much trouble.
'You just have to play smart,' said Singh, who won this tournament two years ago in a four-hole playoff.
Jeff Maggert was in the group at 68 after finishing with two straight birdies and one par that made him particularly proud, given how the wind began to blow hard in the afternoon. On the 491-yard ninth hole, he hammered a drive down the middle and still had a 2-iron to the green to 18 feet.
Stephen Ames, who will defend his title at The Players Championship next week, challenged for the lead until dropping shots on the 15th and 18th, both courtesy of the swirling wind, and was among those at 69.
Phil Mickelson got away with some shaky shots with his short game and shot 70, while defending champion Jim Furyk and Ernie Els were among those at 71.
'It wasn't just the driver, it was the irons, it was the 3-woods off the tee,' said Mickelson, who began working with Butch Harmon two weeks ago and said he would call him after his round. 'I didn't strike it as well as I wanted to. I didn't get in a rhythm.'
Harrington wasn't sure what to make of his round.
'I've been well in control, knowing what's happening,' he said. 'Today wouldn't have been one of those rounds, I've got to say. It would be nice getting everything going together, holing putts and playing well.'
The putting held him together in the first round at Quail Hollow.
Starting on the back nine, he missed the 11th green long and saved par with a 10-foot putt, then holed an 18-foot par putt after putting his approach into the bunker on No. 12. Facing one of the most dangerous shots on the course, however, he started making things easier.
From the right rough on the 351-yard 14th, with the green running away toward the lake, his sand wedge rolled to a foot for his first birdie. He went over the green on the par-5 15th and chipped to 3 feet, then made it three straight birdies with a 15-foot putt.
The Irishman picked up his next batch of birdies over a four-hole stretch on the front nine, hitting inside 4 feet on the second and third holes, and making a 25-footer for birdie on the fifth.
He had no bogeys on his card, and really no explanation for such a fine start.
'My focus wasn't as sharp as it could have been,' he said. 'You obviously need to take breaks, but definitely I was not as good mentally as I would have left off three weeks ago.'
Singh's only hiccup came on the 242-yard sixth hole when he missed the par 3 to the left and missed a 6-foot par putt. But he was solid the rest of the way, especially at the end. Quail Hollow has one of the most daunting finishes in golf, with a 217-yard par 3 to a peninsula green and a 478-yard 18th hole into the wind.
He missed the green well to the right on the 17th, but saved par with a 10-foot putt. And he hit his best tee shot on the closing hole, right down the middle, and gladly settled for par even though he gave himself a 10-foot look at birdie.
'Should have made it,' he said. 'But I'm happy with 5 under.'
Woods, playing on the one-year anniversary of his father's death, wasn't terribly disturbed with his 70. He took advantage of three par 5s and twice made good par saves to keep his round going until his shot over the green on the 18th.
'Nobody really went low,' Woods said. 'You just had to hang in there.'
Brad Faxon played for the first time since he learned he had Lyme Disease. He wasn't sure when he was bitten by a tick, but said he would be on antibiotics for 21 days. 'I lost seven to eight pounds,' he said. 'For me, that's a ton.' ... Sean O'Hair withdrew after a 75 for personal reasons. ... Kenny Perry opened with a 77 and cleaned out his locker. 'You have to do what you have to do,' he said, without elaborating. By the end of the round, officials were not aware he had cleaned out his locker and left, and he was not listed as a WD. ... Frank Lickliter was disqualified after signing for an incorrect score. He had a 75.