Fiji's Vijay Singh, who surrendered the world number one ranking to Tiger Woods at the Doral Open last Sunday, had to be content with a one-under-par round at the Country Club at Mirasol.
Singh was joined on 71 by Davis Love III, runner-up the last two years, world number seven David Toms, winner of the WGC-Match Play Championship two weeks ago, and 2008 European Ryder Cup captain Nick Faldo, making his first appearance on the 2005 PGA Tour.
Campbell, who led through much of last month's rain-hit Nissan Open only to lose to Australian Adam Scott in a playoff, racked up eight birdies, an eagle and two bogeys on the Sunrise course to rocket to the top of the leaderboard.
Playing the front nine last, Campbell had a flawless finish to his round, making six birdies and three pars after the turn.
"It was a great day," said Campbell, who will defend his title at Bay Hill next week. "I was able to hang in there at the start and then get things rolling on the back nine.
"I had everythinggoing today, I really made my share of putts, a couple of longer ones," the Ryder Cup player told reporters. "I didn't leave much out there today.
"I'm pretty tough on myself, I expect a lot out of my game. I just go quietly about my business."
Wetterich had a bogey-free round to take sole possession of second place at six-under 66, one ahead of Sweden's Jesper Parnevik.
A resident of nearby Jupiter, Parnevik, who has not lifted a title since his 2001 Honda victory, dropped only one stroke all day, on the par-four 18th.
"That 64 (by Campbell) was really pretty good," said Parnevik, who turned 40 on Monday. "It had to be one of the best rounds of the year because I'm really happy with my 67.
"It was very windy and these greens are not easy, so five-under I'm very pleased with."
Australian Aaron Baddeley shared fourth place on 68 with Americans Woody Austin and Nick Watney.
Todd Hamilton made a solid start to the defence of his title with a three-under 69. Only Jack Nicklaus has ever won back-to-back Honda titles.
Hamilton arrived at Palm Beach Gardens last year as an unheralded journeyman searching for his first PGA Tour victory but returns as the defending champion and British Open winner.