Yes, there's a difference. Whenever you reposition a speaker the sound will be affected. What you want is to be as close to on-axis to the tweeter(s) as possible.
This will vary from speaker to speaker, depending on the driver alignment and how well (or poor) they image. Some speakers do not have good off axis performance, and if you place the speakers in a way that you are off axis from their "sweet" zone, the sound could be affected negatively.
Your room will also have some affect. The bottom line, as Jack points out, is yes, it will make a difference. The simplest answer really, as it always is with speaker placement, is experiment with some different positions and see how it sounds.