Masters champion Mike Weir and two-time U.S. Open champion Lee Janzen opened with 2-under-par 68s and share fourth place.
Tiger Woods, who is majorless coming into the PGA Championship for the first time since 1999 when he went on to win at Medinah, posted his highest opening round in a PGA Championship with a 4-over 74.
Woods, the winner in both 1999 and 2000, holed a 25-foot, left-to-right birdie putt at the 13th but found trouble at the next two holes. He left a chip on the fringe at 14 and hit such a poor chip at 15 that he threw his wedge at the bag and walked to his ball before it stopped. Those holes resulted in bogeys and things did not get better for the No. 1 player in the world.
Woods bogeyed three and seven and did well enough to make par from the rough at No. 8. At the ninth, Woods drove into the right rough and muscled his second short of the green on the left side. His third stopped three feet from the hole but Woods missed his par save on the right side and left with another bogey.
He is tied for 58th place with among others Davis Love III and Fred Couples.
'I just didn't drive very well and put myself under a lot of pressure because of it,' said Woods, through a PGA media official as he did not speak to reporters. 'It didn't matter what club I hit off the tee. I couldn't keep it in play.'
Woods was not the only top-notch player to struggle on Thursday. Defending champion Rich Beem posted the highest score in the first round by a returning champion since the tournament moved to stroke play in 1958 with a 12-over-par 82. He was joined at that number by Brad Faxon and Colin Montgomerie, who finished second last week at the Nordic Open on the European Tour.
Darren Clarke and Justin Leonard shot 79s, Thomas Bjorn a 78, Retief Goosen posted a 77 and 2001 winner David Toms, Kenny Perry and British Open champion Ben Curtis all shot rounds of 75.
But Mickelson outplayed almost everyone on Thursday. He teed off on 10 and birdied his opening hole as well as the 12th. He sank a curving 15-footer for birdie at the 13th to go 3-under par over his first four holes.
Mickelson dropped his first shot of the tournament at the 495-yard 17th but answered one hole later with a 12-footer at Oak Hill's demanding closing hole.
The left-hander birdied the second hole and nearly holed out for eagle at the fourth when his chip skimmed past the hole. Mickelson parred the next four holes but found trouble at the ninth, when his seven-footer for par missed the hole to drop Mickelson out of sole possession of first place.
'I felt like I played well and shot 4-under on a very difficult course,' said Mickelson, who finished second to Toms in 2001. 'I did a number of things well today. I felt like I putted well and drove it pretty good off the tee.'
Mickelson's history in major championships is well-documented. He is 0-45 in majors and this year, Mickelson is winless on tour and only 26th on the money list. Mickelson tied for sixth last week at The International but downplayed his early lead.
'It's Thursday, there's a lot of golf left,' said Mickelson. 'Everybody wants to get off to a good start. It's tough to play catch-up in a major championship.'
Pampling began on No. 10 and hit several good shots into the first three greens but got no putts to fall. Pampling knocked his approach to three feet at 13 and sank the putt for birdie. He made it back-to-back birdies at 14 when he holed a 30-footer.
On the first, Pampling drained a 10-foot birdie putt and ran one home from the same distance at No. 8. He drove into a bunker at nine but was able to get up and down and save his spot atop the leaderboard as the only player in the field to post a bogey-free round.
'It was just nice all day. I drove the ball really well,' said Pampling, who is in his second full season on tour. 'I had two tee shots that went into the rough so I really didn't have to deal with the rough all that much, which obviously made it a little bit easier. I hit some nice shots and made some putts. It was pretty boring but I'm happy with it.'
Pampling is participating in his third major championship and the memories of one of his previous starts may haunt the Aussie Thursday night. At Carnoustie in 1999, Pampling shot an opening-round 71 for the first-round lead but carded an 86 in the second round and missed the cut.
'Obviously, it's the first day and there's still three more to go, but it's a nice position to be in, that's for sure,' said Pampling, whose clubs were stolen from his garage in mid-April.
Vijay Singh, the 1998 PGA Champion, Chad Campbell, Fred Funk, Aaron Baddeley, Tim Herron, Shaun Micheel and Kevin Sutherland share sixth place at 1-under-par 69.
Robert Allenby recorded the first ace in a PGA Championship since 2001 when he holed a 4-iron at No. 11. He shot an even-par 70 and is tied for 13th with notable players like Jay Haas, Hank Kuehne, who won the U.S. Amateur title at Oak Hill in 1998, and Charles Howell III.