Ben Foden will miss England's QBE autumn internationals after it was confirmed he requires surgery on damaged ankle ligaments.
The Northampton full-back suffered the injury playing against Bath last Friday night and he is expected to be sidelined for between 10 and 12 weeks.
Mike Brown and Alex Goode both started Tests at full-back on the summer tour of South Africa and will be the leading contenders for the 15 jersey.
England open their autumn campaign against Fiji before tackling Australia, South Africa and New Zealand on consecutive Saturdays at Twickenham.Foden has become an integral member of the England set-up since making his international debut in 2009, appearing in 27 of the last 28 Test matches.
"It is unfortunate for Ben who has had a good run in the side and is a valuable leader," Lancaster said.
"But we have a number of back three players who are playing well and this offers a chance for them."
Two of Foden's last three appearances came on the wing in South Africa as Lancaster looked to counter the Springboks' kicking game with two specialist full-backs.
Brown started the first Test defeat before being ruled out of the tour with a broken hand, opening the way for Goode to make his full debut in the drawn third Test in Port Elizabeth.
If Foden is sidelined for 12 weeks, he could also miss the first four of Northampton's Heineken Cup group matches against Glasgow, Castres and the back-to-back fixtures with Ulster.
"Ben had been playing well at the start of this season and to lose him to injury is obviously disappointing," said Northampton director of rugby Jim Mallinder.
"But we know that he is a dedicated professional and will work his hardest with our performance team to come back as a better and fitter player.
"In the meantime Ben's injury will give opportunities for the other back three players like James Wilson, Scott Armstrong and Noah Cato to show what they can do in the Saints first team."
England captain Chris Robshaw hopes the loss of Foden - and any other injury absences - could have long-term benefits for England's bid to win the 2015 Rugby World Cup on home soil as it will give opportunities for other players to show they can step up to the plate.
Tom Croft, Ben Youngs and Alex Corbisiero are also injury doubts for the four-match autumn series.
And Robshaw believes if England are to topple reigning champions New Zealand in the World Cup, they will need to match the All Blacks' strength in depth.
"Unfortunately, injuries are something that happens in our sport and we have to be able to react and have faith in the players coming in, not just to do a good job but do a great job and put pressure on another player to get back in the side," Robshaw said.
"That's what you want in the squad. If you look at New Zealand, if they have a couple of injuries they might go two players deep and still have world-class players in that position who come in and do a great job.
"That's where we want to be as a national side - to have two or three quality international players in every position, so that if someone has to come in, you know they're going to do an excellent job."