Middlesbrough will be forced to continue without Victor Valdes and Gaston Ramirez for their penultimate top-flight fixture.
Boro have not enjoyed a happy return to the Premier League, and their slim survival hopes were ended earlier this week after a 3-0 Monday Night Football defeat against Chelsea.
Speaking on Thursday, caretaker boss Steve Agnew revealed that relegation had been "difficult" to accept an immediate return to the Championship, though he admitted his side "haven't done enough" to retain their Premier League berth.
"We have to move on very quickly. We know where we're at, and we have two massive games to come. We have to finish the season strongly," he added.
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Southampton lost 2-0 to Arsenal earlier this week and are without a win since April 8, but they have passed the 40-point milestone and boss Claude Puel has called on his men to end their winless run at the Riverside.
Aside from Valdes (rib) and Ramirez (pelvis), Agnew has no fresh injury concerns ahead of Saints' visit. Defender Daniel Ayala is back in training after an ankle injury, but his appearance in Saturday's matchday squad is doubtful.
Puel confirmed in his pre-match press conference on Friday that he too has no further absentees occupying his mind. Long-term absentees Charlie Austin (shoulder) and Matt Targett (hamstring) are both back in training and with three games in eight days, the Saints boss could be tempted to utilise his returning squad members.
Middlesbrough have won only one of their last five home Premier League fixtures against the Saints (D1 L3), though this is the first meeting since March 2005.
The Saints, 1-0 winners over Middlesbrough in the reverse fixture, are looking to do a top-flight double over their opponents for the first time since the 1996/97 campaign.
Boro haven't kept a clean sheet against Southampton at the Riverside in any of their last seven league meetings since Mark Schwarzer recorded one in a 3-0 win in March 1999.
Four of Middlesbrough's five Premier League wins this season have come at the Riverside Stadium. However, only Palace (17) and Sunderland (14) have won fewer points on home soil than Boro (18, W4 D6 L8).
Southampton have won three of their last six Premier League away games, having won just two of their previous 12 on the road this season.
Of goalkeepers to play 100 or more Premier League games, only Boaz Myhill (1.73) and Wayne Hennessey (1.71) have conceded more goals per game than Middlesbrough goalkeeper Brad Guzan (1.66, 253 in 152 games).
The last Premier League game at the Riverside Stadium saw four goals scored in a 2-2 draw between Middlesbrough and Manchester City - there hasn't been at least four in back to back top-flight games there since May 2007 (four in a row).
Indeed, the last time this happened in all league games was November 2013 (three in a row) when Middlesbrough were in the Championship.
Middlesbrough have failed to score in 17 Premier League games this season, their joint-most in a single campaign (also 2008-09).
Middlesbrough needed a result to stay up at Chelsea and the gulf between them was unreal. It was men against boys stuff.
Southampton have hit a brick wall and Claude Puel needs to finish with a couple of results, but I'm going to go for Boro here, it's their last game at home in the Premier League and there's no reason for them not to go out on the attack and have a go.
PAUL PREDICTS: 2-0 (18/1 with Sky Bet)
Middlesbrough are Sky Bet's 14/5 outsiders to grab victory, with Southampton marginally 19/20 odds-on favourites while the draw is priced at 5/2. Manolo Gabbiadini is seen are the favourite to bag the first goal at 4/1 despite his drought while Alvaro Negredo is considered the hosts' main threat at 6/1 to net first. The Saints are 7/2 slip into the bottom half of the table come the end of the season, while Boro are 3/1 to bounce back from their relegation by winning promotion next season.