Roddick was pushed to the limit by 20-year-old Canadian Milos Raonic before winning 7-6 (9/7), 6-7 (11/13), 7-5, smacking a diving forehand passing winner on match point in what he called the greatest shot of his career.
Roddick made his pro debut at Delray Beach in 2000 but has not played in the $442 500 Florida event since 2003, his best showing a 2002 runner-up effort.
After battling mononucleosis, a viral infection, last year, the 28-year-old American wants to take no chances with what has him feeling bad this time.
"I felt like I got hit by a bus," Roddick said. "I woke up this morning and my bed was soaking wet from sweat. It's just unfortunate timing for this sickness. I honestly don't feel like I can go out there and give it my best.
"I need to get better before I can play again."
Roddick, who will head home to Texas to meet with doctors, is set to lead the US Davis Cup team next in a first round tie at Santiago, Chile.
Australian qualifier Marinko Matosevic took Roddick's spot in the draw against Israel's Dudi Sela in the first round.
Mardy Fish is the second seed at Delray Beach followed by US compatriots Sam Querrey and John Isner.
Querrey, a wild-card entrant, opened with a 6-3, 5-7, 6-3 victory over Germany's Dustin Brown while Frenchman Florent Serra dispatched Ryan Harrison, another American wild card, by 3-6, 6-3, 7-5.
American James Blake swept past Germany's Benjamin Becker 7-5, 6-4, and in the late match, Russian Teymuraz Gabashvili (RUS) outlasted Isner 6-4, 5-7, 7-6 (15/13).