Are we talking in terms of challenge or presence throughout game?
Because by general villanous terms, by which I mean how effective of a villain they actually are, Ganondorf from OoT wins hands-down. The buildup is perfect in that game, the effects he has on the world are very palpable, you get a sense that this guy is someone who must absolutely be taken down to restore the world to its previous state. And the end fight is still the most climatic one I've ever seen.
But if we're talking about how much of a challenge they present to the player, Demise wins hands-down. Even after all this time he manages to kick my *** over and over, and I can only barely manage a victory after a good half-hour of fighting with like only 3 or 4 hearts left (even after using all my potions and every trick in my book). This guy is without a doubt the hardest single foe I've ever faced off against.