When Appalachian State beat Michigan earlier this year, there was some discussion as to where it stood among the greatest upsets ever, and a preseason top 5 team losing to a Div I-AA school at home certainly ranks among the great upsets of all time.
But as was pointed out at the time, it wasn't the biggest upset in terms of the point spread.
USC losing to Stanford, though, might very well be. Stanford was a 38 point underdog when the line opened, and I saw 41 points somewhere as well, making the Cardinal win, quite possibly, the biggest upset in the history of college football.
Here's a link to some other great upsets:
http://www.gamblingonlinemagazine.com/article-detail.php?articleID=3141985 Oregon State (+36) tops Washington, 21-20
1985 UTEP (+36) over BYU, 23-16
1972 Missouri (+35) beat Notre Dame, 30-26
1974 Purdue (+34) at Notre Dame, 31-20
1992 Iowa State (+29) over Nebraska, 19-10
1969 San Jose State (+29) at Oregon, 36-34
1995 Northwestern (+28) over Notre Dame, 17-15
1942 Holy Cross (+28) beats Boston College, 55-12