Originally Posted by JessicaTi
It could be some tagging errors, especially with a library that large. If you haven't already tried it, run syncmyitunes which will catch the easy errors.
If that doesn't work, try Media Monkey or MusicBrainz or another media manager which will do an even more thorough job in identifying errors in the media.
Things like unicode and left over hidden files (usually from Apple) can also cause problems.
Basically, you want to give your music library a good scrubbing.
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Some of your files might have bad ID tags. With such a large collection of music this is probably not what you want to hear.
I had to fix my collection when I bought the car but Sync would still go into an infinite indexing loop once in a great while and reinserting the stick was a workaround.