I have a problem with one of my knees and have always used Looks with no problem. Right now I use the Look Keo pedals and really like them.

On another bike I have spd pedals and for longish rides (20+ miles) on that bike my knee sometimes bothers me. Could be because I am more used to Looks or maybe because of my particular knee issue, I'm not sure, but I do prefer the Looks, overall I just find them more comfortable.