From a fellow Canadian here...

I was actually contemplating the same question not that long ago, as I started into my most recent WIP. I really waffled about where to set it, but did, in the end, go with what my gut had said: Toronto. I'm currently closer to Ottawa these days, but I spent several years in Toronto, and grew up in the GTA, so that's the Big City I know best. And now that I'm writing I'm glad I did, because when I need to think of a destination or location, the names and city layout come easily to me; I think the story will reflect that.
I just finished reading John Green's The Fault In Our Stars. It's set in Indianapolis, which is an unusual choice for a city (writers often gravitate to the big-name cities - New York, LA, Miami). I found it interesting to note, after I'd finished, that he himself lives in Indianapolis.
As for Canada, I was surprised when I picked up bestselling author Kelley Armstrong's latest novel, The Gathering, and saw it was set in rural Vancouver Island. She's from Sudbury, it turns out. Bestselling author Robert J Sawyer set his YA trilogy WWW in Waterloo (he's from Mississauga). Award-winning author Tim Wynne-Jones' latest book, Blink & Caution, is set in Toronto (he's from near Ottawa).
I think probably the main thing to remember with setting is that your readers might be less familiar with your Canadian city than they would be with the big US ones. Everyone knows Times Square and Central Park and Staten Island, even if they haven't been there, but not everyone knows Nathan Phillips Square and High Park and the Toronto Islands. Just make sure you give the reader a context for the action, since they won't be able to fill it in from their own knowledge.
More important than the setting is the culture - if your culture feels familiar to the reader, it doesn't matter where the story is set, they'll still be able to relate. And since Canadian culture is, for the most part, very similar to American culture, you should be okay.