Harlequins Women will play at Twickenham for the first time against Irish champions Leinster in December.
Last season's Premier 15s runners-up will feature on Saturday, 28 December.
The match is part of Big Game 12, Harlequins men's annual Premiership game at Twickenham, which this year sees them face Leicester Tigers.
Harlequins Women are top of the Premier 15s table with six bonus-point wins from six games, including a 101-0 win over Richmond on the opening day.
"We're always buzzing about the big games that are happening, so for us to be part of Big Game 12 we're really excited," said Quins captain Rachael Burford.
"It's a great opportunity to play against a strong Irish province team, they're back-to-back champions so we have to respect that and I think for our girls, there are a lot who have not played against other international players.
"What better stadium to play than the home of English rugby at Twickenham? It is going to be a phenomenal opportunity."