In high school, easily AP Calculus. My friend John and I were in a never-ending competition to see who would get the worst grade in the class, and who would get the second to worst. (Although, admittedly, it became a very, very crowded field by the end of the year and neither of us ended up with the worst final average.) I remember for our final project we spent hours and hours locked in the library with every calculus book we could find while trying to work our way through the nine most devious calculus problems our teacher was able to invent. (Even though there was a lot of cheating going on in the class, neither of us ever did. The fact that we weren't able to, because no one would ever, ever want to copy from us, may have played a part in that.)
In college, I'd probably have to say the James Joyce class I took. The first two weeks were easy enough--all I had to do was read The Odyssey for about the sixth time in my schooling career. But after that, it was Ulysses, and nothing but Ulysses. And I have never struggled so hard in my life to write such bad papers. One time I lurched in to class after an especially hair pulling episode, unshaven, unwashed, to hand in my paper, and he greated me with "Ahhh, Mr. McGinn, fresh off the presses I presume?" To which I wittily replied "Hrghmmbldgrgrgr" and flopped in a seat in the shade.
For I reason I never fully figured out, he still gave me an A in the class, despite my papers never having gotten better than a B+. I think my girlfriend at the time reminded him of one of his ex-wives and he just took pity on me.