New York beat Miami in last October's Wembley game
The New Orleans Saints will play the San Diego Chargers at Wembley Stadium on 26 October, the NFL has announced.
It will be the second regular-season game to be played in London after Wembley hosted the New York Giants and Miami Dolphins in October 2007.
NFL commissioner Roger Goodell said: "We have great expectations for the game and for the event."
Goodell also endorsed a recommendation to play at least one game in the UK in each of the next three years.
"Playing a limited number of regular-season games internationally will help build and grow an already passionate international fan base," he said.
"We think this game will be great for the UK fans but also the people of New Orleans and Louisiana, and the people of San Diego and southern California.
"This is a great opportunity to go on an international platform and promote the things that are happening in their cities."
The announcement was made in Phoenix, Arizona, ahead of Sunday's Super Bowl XLII between the Giants and the New England Patriots.
A crowd of 81,176 came to Wembley in October to watch the Giants beat the Dolphins 13-10 in muddy conditions in the first-ever NFL regular-season game to be held outside the Americas.
NFL bosses were delighted with the attention the game received, both in the UK and around the world.
NFL UK managing director Alistair Kirkwood said: "Clearly, the fans' enthusiasm convinced the NFL that the UK should be rewarded with another game in 2008.
"We are very excited as we begin preparations for that and conclude this season with BBC TV showing its first-ever Super Bowl."
Murrayfield in Edinburgh and Cardiff's Millennium Stadium were also mentioned as potential venues for the second UK match.
Wembley came under fire for the standard of its field after a rain-hit game, in which players struggled with their footing.
The turf was still a problem a month later, when England's football team crashed out of Euro 2008 with defeat to Croatia.
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