Barry Petchesky of Deadspin today speculated that the week 6 matchup between the Jaguars and the Broncos could have the largest point spread in NFL history. According to a tweet from RJ Bell, Jay Kornegay, director of the Las Vegas Hilton sportsbook, puts the point spread at 28 points.
According to my rankings (as of September 30*), that number seems a bit high. The Broncos' GPF (Generic Points Favored) is 8.7 points. The Jaguars' GPF is -11.5 points. Factoring in a generic home field advantage of 2.5 would imply a point spread of 22.5. According to sportsdatabase.com, there have been two games since 1989 with a point spread at least that high.
Early week 6 lines should be available soon, so we'll see where they start the spread and how it eventually closes.
* There was an error in the rankings table that has since been corrected. The original version of this post had a predicted point spread of 21.5.