Mark McNulty, John Harris, Walter Hall and Tom McKnight are knotted in second place at 5-under-par 67.
Thompson parred his first two holes, then broke into red figures at the third when his 8-iron approach stopped 4 feet from the hole. He made it two in a row with a 12-footer for birdie at the fourth.
He found trouble at No. 7 when his 8-iron approach landed in the right rough. Thompson bogeyed the hole, but made up for the miscue with a 35-foot birdie putt at the par-5 ninth to make the turn at 2-under-par 34.
Thompson three-putted the 10th green for a bogey. Once again, he reclaimed the lost stroke immediately as he tapped in a 3-foot birdie putt at the par-4 11th.
Thompson started a strong run of golf starting at the 14th. He hit a 4-iron to 15 feet, but missed that birdie try. That would be the last squandered opportunity for the 58-year-old.
He drained an 18-foot birdie putt at the 14th, a 17-footer for birdie at 15 and a 23-foot birdie putt at 16 to polish off three in a row. Thompson secured the lead with a 20-foot birdie putt at the par-5 closing hole.
This marked the first time in his Champions Tour career that Thompson has held the first-round lead by himself. Three times before he shared the opening-round lead, but now Thompson has first all to himself.
'It was a good solid start,' said Thompson, whose last win on the elder circuit came at the 2001 Enterprise Rent-A-Car Match Play Championship. 'You better do something fast out here because guys are coming up your back.'
One of those coming up his back is McNulty, who is currently second on the tour in scoring average.
He tallied a pair of birdies on his first nine, but missed a 20-foot birdie putt at the par-5 10th. McNulty dropped a shot to par when he three-putted the 11th, but got that shot back with a 10-footer for birdie at 12.
McNulty rolled in a short birdie putt at the 15th, then converted a 25-foot birdie putt at No. 16. He finished off his round with a two-putt birdie from 40 feet at the last.
'I played nicely today,' said McNulty, who is ninth on the 2005 Champions Tour money list. 'All in all, my ball-striking was good. I made a 10-footer at No. 12 and putted well after that.'
Harris was flawless on his round Friday with five birdies and no bogeys. Hall and McKnight each mixed six birdies and one bogey for their opening-round 67s.
David Eger, Jim Ahern, John Bland, Ed Dougherty, Don Pooley, Jerry Pate and the leading money winner this year, Dana Quigley are tied for sixth place at 4-under 68.
Defending champion Craig Stadler managed an even-par 72 and is tied for 34th place.