Probably going to be Lost. I'm 3 episodes in as of 2008 and haven't gone back yet...if I ever do, it will be the longest to get into for me by far.
In seriousness though...As others have said, The Office and Parks & Rec took me about a season to get into.
Arrested Development, I admit, took me a few episodes.
Always Sunny took me about a season...I think just to get into a groove of the style or something, I dunno.
Is that the same as skin cancer?