I'd say for me it would be The Kite Runner. They changed so much of the plot that it was almost a different story. The Handmaid's Tale is more excusable because the book is practically impossible to translate into picture format.

Come to mind..

The Time machine
Beowulf
Eragon
Charlie and the Chocolate Factory

The Thing from Another World: A good movie as it's own but as an adaptation of the novella "Who Goes There" by John W. Campbell, it's poor since it's nothing like the story and the monster was very different as it wasn't the shapeshifting parasite from the story because in the 50's they had limited special effects technology, so instead they changed it to a killer walking slumbering plant monster that sucks blood and didn't imitate anyone or devour anyone.

The 1982 version from John Carpenter remains to this day, the quintessential more faithful adaptation of the story.

The Kite Runner was a letdown. The Lovely Bones was a bummer too, because the book was so moving and Peter Jackson is a masterful director.

WHo framed roger rabbit has almost nothing at all in common with the book it was based on (who censored roger rabbit).

The Bourne Identity is very different from Robert Ludlums source novel but I still love that movie and I generally understand that most movies adapted from novels have to either change things or leave things out or we'd be watching 12 hour long movies!

Also, I'm going back and forth on my opinions of the Hobbit adaptations. It would be against my Tolkien appreciation to complain about having this much screen time, yet I felt exhausted midway through Desolation of Smaug.

The Seeker: The Dark Is Rising. I never read that book, but
I heard the guy who directed the movie didn't either. I think
he was also quoted as hating the entire fantasy genre. That's
probably why the film isn't really that well liked.

The Hobbit happened to be my favorite novel. The movies were a let down. All I ever wanted to see was a good live action Hobbit. But no, we had to have Lord of the Rings first and better made than the Hobbit trilogy!

^Is very difficult to translate literature/novels into screen let alone LoTR/Hobbit universe. The Hobbit is one of my top 10 reads ever and even if they deviate considerably the movies are masterpiece material.

City of Ember. The book was a YA masterpiece and I actually got ANGRY at how messed-up and childish the film adaptation was. What a waste of great material.

Dogs Of War very different from the book and No Country For Old Men.

The Princess Diaries 1 and 2 [Disney/Buena Vista]
The Princess Bride [MGM Studios]
The American Girl Film Series [Various]
Charlie and the Chocolate Factory [Warner Bros.]
Bridge to Terabithia [Disney/Buena Vista]
DreamWorks Captain Underpants: The First Epic Movie [DreamWorks Animation]
Clueless [Paramount]
Little Women (1994) [Columbia]
Emma [Disney/Buena Vista]
Freaky Friday (1976) [Disney/Buena Vista]
Charlotte's Web [Paramount]
Holes [Disney/Buena Vista]
Ramona and Beezus [20th Century Fox]
Horton Hears a Who! [20th Century Fox]
The Hunger Games [Lionsgate]
James and the Giant Peach [Disney/Buena Vista]
Lord of the Flies [Orion Pictures]
The Lord of the Rings (series) [New Line Cinema]
Maniac Magee [Nickelodeon]
Of Mice and Men [MGM Studios]
Where the Wild Things Are [Warner Bros.]