"What a great opening — again!" Cancellara said.
Giro D'Italia winner Ryder Hesjedal of Victoria was tied for 14th place, 18 seconds back.
France's Sylvain Chavanel was third, also seven seconds back, after the winding 6.4-kilometre time trial in Liege.
Swiss veteran Cancellara is unquestionably the world's best time-trial rider, but isn't considered a Tour contender because he, unlike Wiggins, often struggles in the mountains. Cadel Evans of Australia began his title defence in 13th place, 17 seconds behind Cancellara.
"I did the most I could. It's not always easy. I always do the maximum," Cancellara said after winning in seven minutes 13 seconds at an average speed of 53 kilometres per hour. "It's a great feeling and this certainly takes some of the pressure off."
All of Cancellara's prologue victories have been outside France: The first was in the same Belgian city in 2004, beating Lance Armstrong by 2 seconds, then London in 2007, Monaco in 2009, and Rotterdam in 2010.
At the first time check, around the midway point, he led Chavanel by one second, then accelerated to the finish.
Wiggins, a three-time Olympic champion who is hoping to be the first Briton to win the Tour, said he believed going into the prologue that "there was a man who could beat me: There is always Fabian, he is the best in the world" when it comes to time trials.
"I finished second, so that's a good thing," added Wiggins. "Physically I felt fantastic. I didn't take any major risk because there were a lot of tricky sections."
Evans, too, said he'd expected to be outclassed in the short prologue, and put his ride into a broader perspective.
"Not good, but not bad," the Australian said. "Of course I'd rather concede less seconds, you never want to lose time ... I've got one (general classification) rider ahead of me, but I was kind of half-expecting that. Wiggins, what his background is, is these short efforts."
"For me the real racing starts tomorrow," Evans added. "I'm just happy to get it going, and looking forward to some good racing. ... It's like six kilometres out of 3,500 or so, so in that regard it's a small comparison."
The Tour start offered a welcome return to racing — the entree into three weeks of criss-crossing France, nosing into Switzerland and scaling climbs in the Alps and Pyrenees before the July 22 finish on Paris' Champs-Elysees.
Despite jittery first-day nerves, only a few riders ran into mishaps. Tony Martin, the reigning world time trial champion, was the day's highest-profile casualty: The German rider got a flat tire, raised his hand to his team staffers, and had to change bikes — and crossed 15 seconds back of Chavanel, who was leading up to that point.
Promising young Slovak rider Peter Sagan briefly skipped off the road and lost time.
The victory offered a bright spot for Cancellara's RadioShack Nissan Trek team, which is without its leader Andy Schleck of Luxembourg — out nursing a spinal injury sustained in the Criterium du Dauphine this month. The team is also without manager Johan Bruyneel, who's been listed in a U.S. Anti-Doping Agency doping case also focusing on Armstrong. Bruyneel chose to stay away so as not to be a distraction.
In a further embarrassment, Enrico Carpani, a spokesman for cycling governing body UCI, said it received information from several RadioShack riders that they had faced delays in receiving some salary payments. RadioShack spokesman Philippe Maertens said he believed they had been paid, "and if not, there is a reason for it." He called it a "private issue."
Brushing aside the team's issues, Cancellara said he was focusing "on what I have to do — and that's riding my bike." He said the victory, which he dedicated to his pregnant wife, was doubly rewarding because he broke his collarbone in the Tour of Flanders in April and wasn't sure he'd be at his best for the Tour prologue.
As defending champion, Evans had the honour of riding last among the 198 competitors who rolled down the starter's ramp for the race against the clock in the cycling-crazed city, where untold thousands of fans lined the route.
Sunday's first stage takes riders over a mostly flat, 198-kilometre loop from Liege to the nearby town of Seraing.