I use OpenGL because:
1. It can run at my native resolution (1280x1024) without needing to change the video mode.
2. It can run at my native resolution without either slowing down or having absolutely terrible texture precision (try it - run Software Mode in 1280x1204 or higher and notice how as you go from the top-left to the bottom-right of the screen, the texture jitters like crazy as the camera moves. And for larger walls the artifacts are even worse).
3. Poor perspective is another issue. Anytime you look up or down in Software, all it's doing is vertically scrolling a tall rendering of a scene from a static orientation. In first-person view, if you try to look up or down at all, there is massive distortion, which makes it very easy to become disoriented. If you look too far up or down, the camera will even clip through the floor or ceiling, especially in split-screen mode. It just isn't suitable for multiplayer games. Not to mention, Software breaks apart if you try to make a visible area too large or tall. OpenGL has neither of these problems.
4. It is actually competent with semi-transparencies. Rather than using a nearest-neighbor color matching method on a 256-color palette, it has access to 16-million colors. That means that semi-transparencies and lighting effects don't have nasty banding or washed-out colors. Seriously, gray water is pathetic. If the colormap says it's blue, it should BE blue, damnit.
5. Choice of image filtering. OpenGL gives you the choice of using either nearest-neighbor or bi/trilinear for filtering of textures. Because it's OpenGL, you can also turn on Anisotropic filtering, which will make distant textures render the way they should: without graininess nor blurriness.
6. Because OpenGL is a modern API, you get extra features that can't be replicated as easily in Software. Vanilla SRB2 has the lights that you get in OpenGL (Super Sonic, Emeralds, etc.), which is a nice touch. SRB2JTE and PrettySRB2 also have shadow-casting for all Things, and there are certain distributions of SRB2JTE that will even make all Thing geometry spaz out like crazy (done purposefully, mind). I haven't seen any of that stuff done in Software.
7. It's friendlier with Fraps, as video-recording doesn't run as slowly, and under some instances the counter won't show up in Software (seems to happen for some, though it shows up for me). It also doesn't make PrintScreen mess up the colors, though I use Fraps for pictures like that anyway.
In closing, yes, OpenGL.