The San Francisco 49ers will return to Wembley, this time as the away team, to face the Jacksonville Jaguars in next year's London NFL fixture.
The Jaguars have already been announced as the home side between 2013 and 2016 and their owner Shad Khan confirmed that the first opponents will be the 49ers, who beat the Denver Broncos at Wembley in 2010.
"Everyone associated with the Jacksonville Jaguars is very much looking forward to our four home games in London through 2016, and we're particularly thrilled and honoured that our first opponent will be the San Francisco 49ers," Khan said.
"This is a unique and important opportunity for the Jaguars franchise, as well as for our fans and community. To share this stage in our first year at Wembley with a rising power like the 49ers will bring additional attention and respect to what we're trying to achieve as a franchise."
Chief executive officer of the 49ers, Jed York, was delighted that his side will again be visiting Wembley.
"The 49ers are excited and privileged to once again serve as ambassadors for the NFL and the game of football internationally," he said.
"Our 2010 experience in London was tremendous. The atmosphere at Wembley Stadium on game day was electric. The ability for us to share 49ers football with our faithful fans internationally is a treat for everyone in our organisation."
The fixture will take place on October 27 next year.