Which genre affords better game mechanics? Is it more fun to sling spells around, or raise hell with heavy machinery? Would you rather be a wizard or an alien? Do you feel more immersion when playing in a universe where magic works, or do you have to have rational physics to believe in a given reality? Let's take a look and see what the real differences are, if any.
First, let's start by defining our terms. Fantasy we'll take to mean "pertaining to a universe which adheres to the elements of fantastical fiction, including use of magic, mythical creatures, pre-industrial machinery, and typically a class-based social structure". In this genre we can safely place such popular games as the Lord of the Rings series (both MMO and offline), Fable 2, and World of Warcraft. Your character will usually follow a standard mold of either warrior or magic-user, with many cross-breed attributes in evidence among the different titles.
Science Fiction we can define as "belonging to a universe modeled upon the physics and technology of the current time, yet skewed in such a way as to examine the society in which we currently live -- either by projecting into the future or introducing advanced technology to the status quo". Into this category we can place games like the Command and Conquer series, and the Halo series.
Now, there are also games that straddle the line between Science Fiction and Fantasy. The Star Wars franchise, for instance, does feature an overtly technological background with its starships, droids, and travel between planets, but the nature of the Force is inherently mystical, despite the dismissable explanation of "midichlorians". Spore, for all of its touting itself as a game about evolution, allows players to create creatures that are completely fanciful, regardless of biology, and it waves away any explanation of how technology works in that setting.
In fact, looking a bit closer, there seem to be very few "pure" Science Fiction games out there. Some purists like to insist that anything going out further than what's scientifically valid is simply Fantasy with technological trimmings -- the use of psionic powers in Starcraft, for instance, argues against its inclusion into the Science Fiction category, despite the other elements. Deus Ex, with its nanotechnology, might as well be Fantasy itself because the functioning of nanobots are only understood at a theoretical level, not a practical one. It's as good as magic -- it just works, and that's all you need to know about it.
So what's the true distinction between the two genres? It's got everything to do with perception and the role of the hero in society.