Full-backs Ryan Bertrand and Cedric will miss Southampton's visit of Burnley because of respective hamstring and ankle injuries.
The news is a big blow for boss Claude Puel given that both players are his first choice in each full-back roles this season, but their absence opens the door to Matt Targett and Cuco Martina to come in and try and hold down first-team spots.
Striker Shane Long is close to a return, also from a hamstring problem, which he picked up on international duty with the Republic of Ireland.
Puel said: "There is some pain in the hamstring for Bertrand and Long, and Cedric has a problem in his foot with the ligament. For Cedric, it is two or three weeks without training.
"I hope these players come back quickly, because it's important for the group and all these games in a short time to have all the squad available."
Pule has not yet given up hope of having Long in the squad to face Burnley at St Mary's on Sunday afternoon and added: "He is a possibility perhaps. He has a little pain, but we will see this tomorrow in the training session."
Jay Rodriguez could also feature after overcoming a groin strain.
Meanwhile, Puel said he would trade missing out on a 94-year club record for clean sheets if it means securing victory against the Clarets.
Saints are bidding to register their seventh consecutive shut-out, with their defence unbeaten since a 2-1 defeat to Arsenal on September 10.
They are now just two clean sheets short of matching a club record that stretches back to 1922, when Southampton managed eight in a row.
"I prefer to lose this record and win the game, it's not important for me," Puel said.
"Of course it's interesting because you show you are strong and with a good solidarity but most important is to win the game.
"If you can score two or three goals it would be fantastic, even if you concede one or two goals. It is not a problem for me."
Burnley have failed to score in any of their three away matches this term while Southampton currently boast the third best defensive record in the top flight.
"It's not just the defence, for me it's important to consider it as the work of all the team - midfield and offensive players also," Puel added.