In 2004, Cancellara, then a twice junior time trial world champion, snatched a first significant win at the professional level when he upset American Lance Armstrong by two seconds in the opening prologue around the Belgian city.
Since then the Swiss has appeared almost inspired by stages of the Tour held outside of France, winning all the prologues abroad, in London in 2007, Monaco in 2009 and Rotterdam two years ago.
"It's quite emotional to return to a course that brought me such great memories," Cancellara said at his hotel near Liege.
"Now I don't know exactly how I'm going to feel after my problems this season. But I prepared well and I hope to be ready," he added.
The Olympic time trial and four-times world champion crashed and fractured his collarbone during the Tour of Flanders in April.
He underwent surgery and while he was back on the bike in late May, only began to rediscover form in the recent Tour of Switzerland where he finished second in two time trials.
Cancellara does not have to look far to see where the threats to another prologue win come from on Saturday.
Over 8.9 kilometres in Rotterdam, he beat Tony Martin by 10 seconds, a result that has not been forgotten by the German, who has set some lofty goals for 2012.
"I hope to take the yellow jersey and hang on to it for as long as I can," Martin, who won the final time trial during last year's Tour, said.
"If I can't do it in the prologue, I'll try again in the first time trial in the ninth stage."
"Since the national time trial championship, I (have) spent twice as much time on my TT bike than on my normal one.
"It's an indication of my motivation," he added.
In 2009, Cancellara upstaged Spain's Alberto Contador and Briton Bradley Wiggins in Monaco.
Wiggins, one the favourites for the overall title this year, finished fourth around the streets of London in 2007, but has improved significantly since then.
He already has five time-trial victories to his name this season and narrowly missed out on another two in the Paris-Nice and Criterium du Dauphine races, both of which he won overall.
As well as Wiggins, Swede Gustav Larsson, Slovakia's Peter Sagan, winner of the Tour of Switzerland prologue, Australia's Richie Porte and Baden Cooke, and experienced British rider David Millar, are tipped to feature in the time-trial stages so "Spartacus" is unlikely to have it all his own way.