London Irish will play their "home" match against champions Saracens in New York early next year, in the first Premiership game to be staged overseas.
The round 16 fixture will take place on 12 March 2016 at the 25,000-capacity Red Bull Arena.
"This is an enormous opportunity for our club to gain exposure in one of the biggest sporting cities in the world," Exiles chief executive Bob Casey said.
Premiership Rugby said the announcement was "a significant day" in its history.
"It has taken a number of years and a lot of hard work to bring to fruition," chief executive Mark McCafferty said.
"There are ambitious plans to grow the game in the States and this is the latest stage in that strategy."
The game will take place in the build-up to St Patrick's Day and London Irish hope to attract New York region's significant Irish community.
The club normally play their home games at Reading's Madejski Stadium. Red Bull Arena, in Harrison, New Jersey, is home to Major League Soccer side New York Red Bulls.
London Irish head of rugby operations Glenn Delaney believes taking the game across the Atlantic will help rugby grow its brand globally.
"For Premiership rugby to grow, it does need new markets," he told BBC Sport.
"If you look at Super Rugby, there's a Japanese franchise, an Argentine franchise. Rugby's becoming a global sport at club level.
"We certainly think it will be a roaring success. A lot of people will come, it's a great stadium to play in and great opposition.
"Saracens have got some links over there as well, so it couldn't be better set up."
The United States named three Saracens players in their 2015 World Cup squad, including 54-cap captain Chris Wyles.
Lock Hayden Smith and prop Titi Lamositele were also included in the Eagles' 31-man party.