Mexico City will host an NFL clash between the Los Angeles Rams and the Kansas City Chiefs in the 2018 season.
While no date has been finalised, NFL commissioner Roger Goodell expects the game to be sometime in November.
Goodell made the announcement on Wednesday during his State of the NFL press conference ahead of Super Bowl LII in Minneapolis.
"Over the past two seasons, we have seen the extraordinary passion that exists for NFL football in Mexico," Goodell said.
"We are excited for another memorable event at Estadio Azteca as the Los Angeles Rams and Kansas City Chiefs head to Mexico City in 2018."
Goodell explained the actual date of the game between the two sides, who both made the playoffs this season, will have to fit into the balance of the rest of the league schedule.
The NFL will also hold one regular-season game in Mexico annually from 2019 to 2021.
"We are thrilled to be a part of the NFL's international initiatives once again, and we are excited to face the Rams at historic Estadio Azteca this fall," Chiefs chairman and CEO Clark Hunt said in a statement.
"The support for the NFL in Mexico has grown significantly since our initial trip in 1996. We look forward to returning to Mexico and connecting with a new generation of fans this season."
The game will be a home contest for the Rams, who will play the rest of their home schedule at the Los Angeles Coliseum until their new stadium is ready to open in 2020.
"Southern California and Mexico share strong historic and cultural ties and this game will provide an opportunity to celebrate the special connection between these two regions," Rams owner Stan Kroenke said.
"It is great to be participating in the NFL's international games again and working with the league to grow the game abroad. Mexico has one of the largest NFL fan bases in the world and we are excited to bring Rams football to the millions of fans there."