usually it's play good through first (which is pretty much like playing the game it was 'meant' to be played) and then with whatever I do post first runthrough is somewhere between evil and neutral. I like to try and be as creative as possible, if the game allows it. I think I had the most fun as pure evil, though, by trying to sandman kill as many characters as possible. Levels you up way fast too, so you don't need to repeat a lot of the missions that are been there, done that. I find a lot of the replayability is either about taking out the various fortresses or towns, or trying to explore whatever you've missed.
As for morality, though, I'm tired of the comic book pure good or pure evil in RPGs. Feels more like a two linear RPGs packaged into one, but still, the expansiveness of Fallout 3 makes up for it. ME2 has a great story, but it's told the same way whether you're a boy scout or a dick. However, that your characters are actually at risk in the final mission is great innovation. Honestly, though, I'm tired of change taking so long in games, which is why I'm veering away from RPGs at the moment.