I did enjoy Mass Effect 2 a lot, but I couldn't get over the feeling that it was trying too hard to be mature. That, and the whole thing felt very confined, especially compared to the first game. When I first got to Omega, I was stunned at how beautiful and alive it seemed... that is, until I realized that it only takes about ten minutes to explore the entire place.
Red Dead Redemption doesn't suffer from either of these problems. The story is interesting, well written, and actually relevant. The world is huge, teeming with life of both the human and animal variety, and full of random events and happenings. Not to mention, I find the gun-play immensely more satisfying, thanks largely to the Euphoria physics.
Admittedly, I'm a little biased, because, well, one is a western and the other is... not.