The New York Yankees and Boston Red Sox will face each other in two regular-season games at the Olympic Stadium in London next year.
"We are bringing you one of the best rivalries in baseball," MLS Commissioner Rob Manfred said Tuesday.
Boston will be the home team for both of MLB's first games in Europe on June 29 and 30, 2019. The stadium will have a capacity of 55,000 in a baseball configuration.
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MLB said it also "committed to playing in London in 2020 and our intention is to establish a long-term footprint in the city" as American sports further embrace British fans.
The NFL has played regular-season games in London since 2007, holding 18 games at Wembley and three at Twickenham. Three more NFL games are scheduled for this year, including one at Tottenham's new stadium.
The NBA and NHL have also held regular-season games in London.
"The stadium infrastructure in this city gives Major League Baseball every opportunity to put on a first-class event," Manfred said. "We hope this series will be the beginning of a relationship with London that persists and a continuation of increasing exposure for Major League Baseball in Europe."
MLB has put renewed emphasis on international games since Manfred became commissioner in 2015.
Cleveland and Minnesota played a two-game series last month in San Juan, Puerto Rico, and the Los Angeles Dodgers and San Diego played in a three-game series in Monterrey, Mexico, last week. MLB announced Tuesday that Oakland and Seattle will open next season at the Tokyo Dome on March 20-21.