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Twickenham will host its first NFL game in October 2016 between the St Louis Rams and an unnamed franchise from the NFC East, it was announced on Wednesday.
Earlier this month t he NFL and Rugby Football Union unveiled a partnership which will see the traditional home of English rugby host at least three regular-season games over a three-year period.
The NFL will come to Twickenham on Sunday, October 23.
Also as part of the 2016 International Series, the Jacksonville Jaguars, set to return to London for a fourth consecutive year, will host the Indianapolis Colts on October 2 at Wembley, which will also stage the Cincinnati Bengals' first game in London against the Washington Redskins on October 30.
The NFL's scheduling formula will see St Louis face the Philadelphia Eagles, Dallas Cowboys, New York Giants or Washington.
Wembley hosted three NFL matches during 2015, with October's clash between the Buffalo Bills and the Jaguars played in front of a bumper 84,021 crow. The English capital will also play host to regular-season games at Tottenham's new stadium from 2018.
NFL commissioner Roger Goodell said: "The passion our UK fans have shown for the NFL is overwhelming.
"We are very appreciative of the strong and growing fan support, not only for the games, but for all of the related NFL events we host in the UK throughout the year.
"We look forward to welcoming new fans to their first NFL game in 2016 and welcoming back thousands of others that are helping our sport grow to new levels of popularity in London and beyond."
The game times and a possible additional International Series game outside of the UK will be announced at a later date, the NFL added.
The Jaguars last month extended their commitment to playing NFL matches in London through to 2020.