The deal will begin in October 2016 and is the first of its kind for the RFU. Details regarding the first match will be released later this year.
At least two more games will be staged at the southwest London venue as part of the agreement.
The NFL International Series provides a fertile activation ground for brands, with the likes of Pepsi Max, StubHub and Budweiser activating at the NFL’s 14th International Series game at Wembley on Sunday (1 November).
NFL UK has not currently cemented any plans for brand activation at Twickenham, however it told Event: "We are very excited about continuing to develop activation plans with all of our sponsors at all of our stadiums."
The league has extended its agreement with Wembley Stadium to 2020, while it will pay at least two games a year at Tottenham Hotspur’s new ground from 2018.
Mark Waller, NFL executive vice president of international, said: "We are committed to continuing to grow our sport in the UK and believe that adding Twickenham Stadium to our roster of host venues in London is further evidence of that commitment."
Sophie Goldschmidt, chief commercial and marketing officer at the RFU, said: "The NFL has a strong and growing fan base in the UK, and this, combined with the investments we’ve made in our stadium will give fans more opportunities to experience the action first-hand at a world-class venue. We look forward to working with the NFL on this partnership."
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