For me, it's not the only real one, but this is truly a big problem.
Hit location permits a different protection value on the different locations (as a flak jacket that don't protect arms).
Another one is that it forbids certain tactics (aiming to strike a certain location to disarm, or to hit more vital area).
The biggest problems I have with the major wound table (I'm speaking of the one of SB1, because this is the only one I have used) is that it is completely random. It may be desirable in SB, where the chaos is the driving force, but I don't think it can be desirable in other settings. Besides that, the wounds caused by a broadsword and a firearm are completely different, and require a different table (I don't see how you can cut the nose of your opponent with a colt peacemaker). If we have several table depending on the weapon, it becomes more complicated than managing the hit locations, and if we don't, the wounds can be aberrant.
And I'm not even speaking of the lethality of the combination of Major wound table / Variable armor. I don't care loosing a character because I'm beaten by a superior foe or because I'm doing mistakes, but I don't like to see the death or the unusability of a character just because of sheer bad luck on 2 consecutive dice rolls.
Runequestement votre,
Kloster