Recovering from flu-like symptoms, the 42-year-old Mickelson had three birdies, a bogey and double bogey at La Quinta Country Club — one of three courses used in the pro-am event.
Jason Kokrak, Roberto Castro and James Hahn topped the leaderboard at 9-under 63. Kokrak had two eagles and five birdies at La Quinta, Castro had nine birdies at PGA West's Jack Nicklaus Private Course, and Hahn had nine birdies on PGA West's Arnold Palmer Private Course.
"I felt a lot better," Mickelson said. "I took it easy on Monday and Tuesday. It was like Day 10, but I'm fine now. I'm 95 percent better. I'm not contagious and the energy's coming back. I've been able to practice. I played a little bit yesterday and it's fine."
Kokrak had two eagles and five birdies at La Quinta.
"I just tried to put it in the right spots, put it in the fairways," Kokrak said. "Out there, that's key. They're tighter fairways and if you can be in the fairway, you'll have a good opportunity for birdie."
"It was a great day," Hahn said. "Chipped two in. Hadn't done that since I was nine."
"It was a perfect day," Henley said. "The weather is perfect. The greens were true. So, it's just trying to stay patient and let the birdies come to me."
Mickelson made his first start since tying for second in early November in the HSBC Champions in China, the only event he played after the Ryder Cup.
"My timing and rhythm was off a little bit," Mickelson said. "My putter was atrocious and I've been putting great, too. So, that was disappointing."
Mike Weir, the 2003 champion, opened with a 67 at La Quinta. The Canadian left-hander has missed 16 consecutive cuts and has finished only one tournament — a tie for 70th in the AT&T National in July 2011 — in his last 28 events.
"I drove it well and putted well and everything was pretty good," Weir said. "It was a nice solid round to get off to a good start."
Mickelson is opening a stretch of five or six straight events, a run that will end at Riviera or the Match Play Championship.
This tournament is the first of seven events this year with an expanded field because of the short season. There are 156 players this year instead of 144.
Defending champion Mark Wilson shot a 77 at La Quinta, while Robert Karlsson, the Swede who entered last year at No. 24 in the world and ended up having to go through qualifying school to retain his tour card, had a 71 on the Nicklaus course. U.S. Open winner Webb Simpson shot a 73 on the Palmer course.