Peyton Manning made a sparkling return after a year's injury absence from the NFL, leading Denver to a 31-19 victory over the Pittsburgh Steelers in his Broncos debut.
Manning, the four-time NFL Most Valuable Player who missed all of the 2011 season after undergoing four neck surgeries, completed 19-of-26 passes in front of his new home fans in Denver and joined Dan Marino and Brett Favre as the only NFL quarterbacks to throw 400 career touchdowns.
"It's a tremendous honor -- I don't feel like I belong in their category," Manning said of joining the select club.
Manning is often included in any discussion of the NFL's best ever quarterbacks, but that didn't stop the Indianapolis Colts from dropping him and taking star collegiate quarterback Andrew Luck in the April draft.
The Broncos seized the chance to get Manning, despite the uncertainty that surrounded him.
"It's special," he said of rewarding them with a season-opening win, although he also cautioned that it was "just one game".
Demaryius Thomas caught five passes for 111 yards and a touchdown, while Willis McGahee carried the ball 16 times for 63 yards in the victory.
Manning's 71-yard scoring pass to Thomas in the third quarter was his first as a Bronco and the 400th of his career.
Steelers quarterback Ben Roethlisberger passed for 245 yards and two touchdowns but was intercepted by Broncos cornerback Tracy Porter on a crucial drive in the final two minutes, with Porter racing 43 yards for a touchdown that helped seal the win.
Meanwhile Luck, the man who succeeded Manning in Indianapolis, endured a difficult day in a 41-21 defeat at the hands of the Chicago Bears.
Luck completed 23 of 45 passes with a touchdown, three interceptions and a fumble.
Another highly scrutinized rookie signal-caller, Washington's Robert Griffin III, made an auspicious debut, throwing for 320 yards and two touchdowns as the Redskins beat the New Orleans Saints 40-32.
Late in the first quarter, Griffin absorbed a hard hit from the Saints' Malcolm Jenkins before releasing the ball downfield to an open Pierre Garcon, who raced 88 yards for Griffin's first NFL touchdown.
"I've won a high school state championship and a bowl game in college, but to play in the NFL, the pinnacle of it all, and win your first game against a Hall of Famer in Drew Brees, it's at the top," Griffin said.
Elsewhere on the first full day of the season, New England Patriots quarterback Tom Brady threw two touchdown passes and Stevan Ridley rushed for a career-high 125 yards with one score as the defending AFC Champion Pats defeated Tennessee 34-13.
Philadelphia quarterback Michael Vick threw four interceptions, but atoned with a touchdown pass to Clay Harbor with 1:18 to play to give the Eagles a 17-16 victory over Cleveland, had rookie quarterback Brandon Weeden at the helm.
Mark Sanchez threw three touchdown passes and the New York Jets defence forced four turnovers in the Jets' 48-28 victory over Buffalo.
San Francisco kicker David Akers made three field goals, including an NFL record-equalling 63-yarder, as the 49ers beat Green Bay 30-22 at Lambeau Field.
In other contests, Minnesota edged Jacksonville 26-23 in overtime, Detroit rallied for a 27-23 victory over St. Louis, Atlanta beat Kansas City 40-24 and Houston defeated Miami 30-10, Tampa Bay beat Carolina 16-10 and Arizona downed Seattle 20-16.