The two-time heart-transplant recipient, who tied for second at last year's U.S. Open, took advantage of ideal scoring conditions on a soggy Sedgefield course to join fellow Americans William McGirt and Tom Hoge atop the leaderboard.
Preferred lies and soft greens allowed players to attack the pins fearlessly on a day when 102 players broke par, including Tiger Woods, whose 64 was his best score in over two years.
Woods was followed by a huge crowd despite being one of the early starters - and he did not disappoint the droves that turned up at the crack of dawn, promptly chipping in from 55 feet for birdie at his first hole, the par-four 10th.
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Despite a bogey at the very next hole, Woods finally got his putter working to roll in six more birdies for his lowest round on tour since firing a 61 in the second round of the 2013 Bridgestone Invitational.
His score was soon beaten by Compton, who had an unusual explanation for his success. Compton does not normally drink, but the 35-year-old had a couple after the pro-am on Wednesday after being summoned for a drug test.
"I drank two vodka tonics to get my kidneys working. Maybe I should do that again," Compton joked to reporters.
At 114th on the FedExCup points list, Compton is likely to stay in the top 125 and qualify for the lucrative playoffs starting next week, and a good start here did not hurt his cause.
He arrived after a couple of weeks off and a London holiday with his wife, but knocked off the rust in the pro-am and continued his hot hand when the real action started.
"Kind of an unexpected round," he said after storming home in 28 strokes on his final nine holes, the easier front nine. "It was really a great ball-striking day with a lot of tap-ins and the course yielded some low scores (so) it was just put your foot down and know (it is) going to take a low number to win this week."
Co-leader McGirt, who grew up in nearby Charlotte, teed off so early that it was hard to read the greens for the first few holes on a cloudy morning.
"It was a little dark early but I played pretty solid all day," said McGirt, who is ranked 86th in the tour standings and, as with Compton, has never won on tour.
Tour rookie Hoge, in the last group of the day, birdied the 18th to make it a three-way tied for the lead.
Compton and McGirt led a group of four players by one stroke, while two-times major winner Martin Kaymer was among those who matched Woods on 64.
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