Manning will be looking for a bit of revenge Sunday night as the Denver Broncos host the Saints, who play their first game under interim coach Joe Vitt.
A lot has changed since that matchup in February 2010. Of course, Manning is no longer donning an Indianapolis Colts uniform. And the Saints -- having started 0-4 -- aren't exactly looking like Super Bowl contenders, though they've won two in a row.
But other things -- like Manning and Brees starring as two of the league's top quarterbacks -- are still the same.
"Both guys are first-ballot Hall of Famers," said Denver cornerback Tracy Porter, whose interception return for a touchdown sealed the Super Bowl for the Saints. He will face his former team for the first time, now on the same side as the quarterback he picked off.
It took a quarterback of Peyton Manning's caliber to pull off this kind of comeback.
After the Denver Broncos slogged through a nightmare of a first half, Manning showed that he's still one of the NFL's best.
Manning threw three touchdown passes in the second half and Tony Carter and Chris Harrisscored off turnovers by Philip Rivers as the Broncos overcame a 24-0 halftime deficit to shock the San Diego Chargers 35-24 on Monday night.
"It sure was special considering what was on the line," said Manning, a Super Bowl winner and four-time NFL MVP who's in his first season with the Broncos.
Manning was 13 of 14 for 167 yards in the second half for the Broncos (3-3) who tied the Chargers (3-3) atop the AFC West.
But not before Manning nearly pulled off another fourth-quarter comeback in a career filled with them.
In their 13th meeting, and first since Manning left the Indianapolis Colts, Brady directed four scoring marches of at least 80 yards, and the Patriots won 31-21 on Sunday. He's 9-4 in his career against Manning.
"Nobody I'd rather have than Tom Brady," New England coach Bill Belichick said, "but Manning's a great player."
Manning had led his teams back in the fourth quarter to 36 comeback wins. And the Broncos (2-3) rallied from a 31-7 deficit with about five minutes left in the third quarter on Manning's scoring passes of 2 yards to Eric Decker and 5 yards to Brandon Stokley.