Without question Yiazmat from FFXII - the bastard has over 50 million Hp (most party attacks are limited to the usual 9999 damage), plus he hits hard and has instant death attacks. I don't know how many hours it took me. Thankfully the designers made it so you could exit the fight, save, and come back later and he would still have the same damage that you dealt to him.
More recently Elizabeth Greene from [Prototype]. Even on easy it was a long fight (for that game at least) but on hard it took ages - she has some real cheap attacks, you have very few options when taking her on, plus you have to deal with marines and other infected at the same time. Nightmare. You have to hit her once and then run away or else you're dead, and you need to hit her a lot of times.
More recently Elizabeth Greene from [Prototype]. Even on easy it was a long fight (for that game at least) but on hard it took ages - she has some real cheap attacks, you have very few options when taking her on, plus you have to deal with marines and other infected at the same time. Nightmare. You have to hit her once and then run away or else you're dead, and you need to hit her a lot of times.