London Irish will play their home games at the new Brentford Community Stadium from 2020.
The Championship leaders have reached an agreement with Brentford Football Club to play at the west London stadium, which is currently under construction and will have a capacity of 17,250. It is due to open in 2020.
Irish, who are favourites for promotion to the Gallagher Premiership this season, have played at Reading's Madejski Stadium for the last 18 years.
The Berkshire ground is 30 miles away from Irish's training base in Sunbury, and they have had a long-held ambition to return to west London.
And that is now set to happen for the start of the 2020-21 campaign.
London Irish president Mick Crossan said: "In moving to the Brentford Community Stadium we feel confident that we will be able to attract a larger supporter base to join us as we build for the future.
"We are therefore very pleased to have agreed this deal with Brentford's management, and are looking forward to working closely with them to make the Brentford Community Stadium an outstanding home for us.
"The stadium will be an outstanding venue. It is the right size in a great location and will provide a superb match-day experience for our supporters and sponsors alike.
"I would also like to thank everyone at Reading FC who have made us feel welcome at the Madejski Stadium and are most accommodating landlords."
Brentford Community Stadium will be sited just north of Kew Bridge and is less than a mile from Championship club Brentford's current Griffin Park home.
Brentford FC chairman Cliff Crown added: "We are building a high-quality stadium fully equipped and ready from day one for both Premier League football and Premiership rugby.
"Like us, London Irish has a long history in the area and prides itself on having strong roots in the local community.
"We look forward to continuing to work with them over the coming months to support their successful return to the capital."
Reading chief executive Nigel Howe described Irish as "excellent partners" during their time at the Madejski Stadium.
"As a club, we have thoroughly enjoyed a strong long-term relationship with London Irish, who have been excellent partners for nearly two decades at Madejski Stadium," Howe told the Royals' official website.
"We understand and agree with their decision to move back to their heartland and appreciate that, as Brentford prepare to move into new stadium facilities being built in closer proximity to their Sunbury training base, this is the right time for them to relocate and play their rugby closer to the club's London roots.
"We naturally look forward to working alongside London Irish during the remaining months of their tenancy, and everyone at Reading Football Club would like to wish them every success for the future."