I've felt guilty. Not often, but I have. In Baroque, for example, there are definitely a couple of "what have these hands wrought?" moments.
Mighty spoilers: (I am not even kidding this is brutal)
[spoiler]Baroque is a roguelike. Every run, you're given an Angelic Rifle, for free. This is a big gun with five bullets in it, and it kills any monster in one shot. Any monster. They instantly explode in a burst of light, and white feathers materialize from thin air, falling gracefully to the ground. Think of it as starting every game of Nethack with a superpowered Wand of Death.
Now pretty much every NPC in the game either hates that gun or is terrified by it, not because of what it might do to them but because of what it is (though it's unclear if it's because they know it or just because of a gut feeling on their part). So you're basically encouraged not to use it by nearly everyone you come across; it's made pretty clear that this weapon is bad news. But it's way too useful to just leave behind.
In fact, there are never any gameplay repercussions, whether you use it or not. There is no alignment counter, no karma system, no good guy/bad guy points. Use it or don't, it makes no difference.
And then, near the end, you learn the truth about the Angelic Rifle. The ammo cartridges are sentient creatures, innocent incarnations of pure pain forcibly removed from a broken, sick God. When shot into monsters they release their pain into them and die in torment.
In their natural form they look like little eyeless baby angels, and every once in a while you can hear their cries, and their screams of "Murderer! Murderer! It hurts!"
I never used the gun again.[/spoiler]
Now that kind of manipulation probably wouldn't work on everyone ([spoiler]"baby angels, really?"[/spoiler]), but I was really digging the plot and atmosphere the game had going on, and it pressed all the right (wrong) buttons.