Cejka, who has two second-place finishes on the PGA Tour, fired a 7-under 64 at the Harbour Town Golf Links in South Carolina. Lee Janzen, without a victory since the second of his U.S. Open titles 11 years ago, shot a 65.
Last year's Masters champion Trevor Immelman was alone in third at 66 while Brian Gay and Ted Purdy were tied for fourth at 67. Ernie Els and Jose Maria Olazabal were in the group at 68.
"I played pretty solid overall," Cejka said. "I hit good shots today and I was putting well. That's the key. If you putt well, it helps a lot."
Cejka underwent neck surgery last September after pinching a nerve at last year's British Open.
"I'm not 100 percent," he said. "But I'm pretty happy in the way my body feels right now. Now it's a good time to start really practicing hard and play a lot of tournaments."
Two-time defending champion Boo Weekley shot a 2-under 69 despite suffering from a sore back.