Well, I have played thru this game 4 times and now the cruddy stuff happens on my 2nd go thru with Sam B and Logan(so far), both games are now corrupt. I did nothing just played and then my saves went corrupt. All my sweet weapons and all the progress is now gone. Why can't Steam and others make games that don't break after they are working correctly. Why go back in and screw with it, just to make everyone upset who paid their good money for the game. I just think that maybe they could improve on the grafix or gameplay and leave the stable stuff alone!
I have had a few issues with second play-throughs also, but since I started modding the shops so I could get good weapons it doesn't matter that much. Following the tips in the modding thread I just come back as a level 50 and get some good weapons and play it again.
No issues anymore with it corrupting the game I'm playing either (before the second play through, though now it seems the third is dicey!). I just start a new one if it goes south after it ends. Somehow I think modding the game IMPROVED the reliability of the thing.
My system is...
Phenom 1100T no overclock (my little cpu monitor seems to indicate that Windows or the game is using all six cores at one time or another though I don't know it that is true of the game itself).
2 ATI 6970's in crossfire
16GB of ram, though it only uses a bit over 5 it seems
Three 1.5TB drives (but mostly for vids, pics, and backup stuff on the other drives)
Asus Sabertooth 990FX MB (I was sorta looking ahead to the Bulldozer should they ever release the darn thing)
Windows 7 Home Premium
I don't get a lag problem unless some other program is tying up the hard drive doing something like auto backup of the main drive, and then only for a second or so.