Seymour is missing. And as the relationship between Seymour and Enid was the main narrative arc of the movie, that's quite a thing. I think the impact of this is to make the comic much less a matter of what I termed "geek porn" in my article about the film. Enid is not framed as a dream girlfriend for the "bookish fellows" of the world; she's subject, not object.
The art class is missing. Not a big thing by itself, but in the film the presence of Seymour and the art class meant Enid and Rebecca were split up a lot of the time. Not so in the book — they're nearly always together. That's a shame, because...
Enid's the one getting a life. And there goes the other big narrative arc of the film, the estrangement caused by Rebecca's embrace of the workaday world while Enid clings to her hipster bubble. Here Enid looks like she'll soon be heading to college while Rebecca is just sort of a hanger-on. This tends to make Rebecca seem a bit like a cipher, even though the book gives her a heftier amount of face time.
The main characters are less charming. This sort of goes hand in hand with the first item, but nevertheless — the ink-and-paper Enid lacks Thora Birch's... impishness? is that the word?... and is really kind of annoying. Rebecca lacks Scarlett Johansson's seen-it-all, "I choose not to notice that I am a sex bomb" vibe. Of course, actors have twenty-four frames per second and multimedia to work with, which gives them a bit more space to establish such things.
Overall the book is still quite good, however.