In chalking up three successive world drivers' championship victories, the German has added his name to the honour roll of winners at almost every track on the circuit.
Only a few races have eluded him, most notably in his homeland Germany, but also the Canadian Grand Prix in Montreal.
The demanding street circuit, with its long straights and slow, tight corners, does not suit Vettel's Red Bull but his failure to win there has had little to do with his car.
In 2011, he seemingly had the race at his mercy when he charged to the lead after a long rain delay only to make a mistake on the last lap, sliding wide and allowing Jenson Button to overtake him for the checkered flag.
"Obviously one of the craziest moments was in 2011," he recalled as he looked ahead to Sunday's Canadian Grand Prix.
"I made my first mistake of the race which cost us the win. But that's racing."
Determined to make amends, Vettel started last year's grand prix from pole position and led the early part of the 70 lap race. But he lost pace over the final laps and was lucky to finish fourth after skimming the wall near the end.
Although he leads the world standings with 107 points, a victory on Sunday is anything but assured.
There have been four different winners from the six races this season. Only Vettel and Fernando Alonso have won twice.
Unlike Vettel, Alonso has tasted victory at the Gilles Villeneuve circuit before, winning in 2006, en route to his second world title with Renault.
Alonso is third in the title race, 29 points behind Vettel, and Ferrari have not won at the track since 2004, when Michael Schumacher was behind the controls.
Kimi Raikkonen, the 2007 world champion, is second on 86 points. He won the season-opener in Australia for Lotus and finished runner-up in three successive races before fading to 10th at the last race in Monaco.
The Finn won in Montreal in 2005 but said it remains one of the most unpredictable events on the F1 calendar.
"Many times the race has been quite a lottery as there seem to be different things which affect it." he said.
"The weather can change a lot, sometimes the tyres or the track aren't working very well, sometimes there are a lot of safety cars, or sometimes another driver runs into the back of you when you're waiting at a red light."
If recent form is any guide, Mercedes could be the team to beat this weekend. Germany's Nico Rosberg has set the fastest times in qualifying to snatch pole position at each of the past three races and won in Monaco.
"Monaco was a fantastic weekend for the team and I'm so proud of the victory that we achieved there. We'll be hoping to maintain that momentum in Canada this weekend," Rosberg said.
Hamilton, who started on pole in China and has two podium finishes this season, is a Canadian Grand Prix specialist, winning in 2007, 2010 and last year.
He is tied with Nelson Piquet for the second most wins in Montreal, trailling only Schumacher, who has won a record seven times.
"The circuit itself is really special," the Englishman said.
"It's very high-speed, great fun to drive and it's definitely a track where late braking helps.
"It's not too far off a Monaco-style circuit where you need a similar set-up to bounce off the kerbs so we should be quite competitive, although looking after the tyres will be our main challenge."
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