The St Louis Rams will face the New England Patriots at Wembley Stadium this October in the first of three visits to London by the team owned by Arsenal majority shareholder Stan Kroenke.
The Rams will be the 'home' team for the October 28 game, and the team confirmed they have reached an agreement to return to Wembley again in both 2013 and 2014 in a bid to build up a fan base in the UK.
"This is a tremendous honour for our franchise, the city of St. Louis and our fans throughout the world," said Kroenke in a statement.
"We are excited about the opportunity to reach new audiences globally. This is a great platform to showcase the city of St Louis to London and the UK.
"We've seen first-hand the increased popularity of the NFL not only in London but throughout Europe. To play a role in that growth over the next three years will be incredible and is a testament to the many good things happening not only in the NFL but also in the St Louis Rams organisation."
The Rams, who played a pre-season game at the old Wembley in 1987, will be visiting London to play a regular-season game for the first time, while it will be a second trip to the UK for star quarterback Tom Brady and the Patriots, who beat the Tampa Bay Buccaneers 35-7 at Wembley in 2009, again playing as the 'visiting' team.
The Bucs, who along with Manchester United are owned by Malcolm Glazer, also played at Wembley last season, losing 24-18 to the Chicago Bears.
The NFL has played a regular-season game at Wembley every since 2007, when the International Series began with a meeting of the New York Giants and Miami Dolphins.
Every game has sold out with the exception of last season's clash between Chicago and Tampa Bay, which suffered from a vastly-shortened window for ticket sales due to uncertainty over the fixture because of a labour dispute which led to a league lockout through the summer.
Under the terms of a new deal that extends the agreement for games to be played at Wembley until at least 2016, the NFL has looked for teams to commit to playing in London over consecutive seasons to build a more consistent presence in the city, which league commissioner Roger Goodell said would be "very powerful and lead us to what we ultimately would like to do - have a franchise here in London".
Speaking about today's announcement, Goodell said: "The response to NFL games in the UK among our British fans has been exceptional.
"We are confident that having the Rams host one game in the UK in each of the next three seasons will allow us to better serve the growing popularity of our sport beyond the borders of the United States."
The Patriots will hope to head to London as defending Super Bowl champions as they are preparing for the AFC Championship game against Baltimore on Sunday night - when a win will send them to Indianapolis.
"We are honoured to be selected for this year's game and eager to return," said Patriots owner Robert Kraft.
"We had such a great experience during our last visit to London. We are proud to have great support from our fans when we are on the road. The United Kingdom is home to some of our most passionate Patriots fans, including the UKPatriots, who are among our most active fan clubs overall, not just overseas. We look forward to another memorable experience."
The game is a rematch of Super Bowl XXXVI, when Patriots kicker Adam Vinatieri kicked a game-winning field goal with seven seconds remaining to give New England their first ever Super Bowl victory 20-17. Since then, the Patriots have gone on to win two more Super Bowl titles, while the Rams have not made an appearance.