In what is their biggest game since promotion, Southampton know that they have to avoid defeat to FC Midtjylland, and must break down the Danish defence at least once whilst doing so.
Saints boss Ronald Koeman also has to get a positive result, either a win or a draw with more than two goals, without his star midfielder Victor Wanyama.
Wanyama, who has been linked to Tottenham and Arsenal during the summer and has reportedly asked to leave, is suffering with a stomach infection and did not fly with the squad to Billund.
Koeman would have desperately wanted the Kenyan powerhouse to have played, as Southampton have looked porous in recent weeks. Considering they only conceded 33 goals in the whole last season, leaking five in the first three games of this campaign is alarming.
But it looks bleaker in front of goal for Saints, having scored just two goals in their opening league fixtures, with the 0-0 against Watford showing how blunt the attack looks without Sadio Mané on the pitch.
The Senegalese forward is arguably Saints’ sole matchwinner, and Koeman will be desperate that he recovers from the hip problem that saw him withdrawn from the Watford game after just 25 minutes.
It’s do or die in Denmark for Saints; aggregate victory would mean Saints would be in the Europa League group stage for the first time ever, just three years after promotion from the Championship in 2012.
Team news
Aside from the aforementioned Mané and Wanyama, Koeman is still without left back Ryan Bertrand and his most expensive summer signing Jordy Clasie.
Young homegrown defender Matthew Targett will continue to deputise at left back for Bertrand, whilst it’s unclear whether the Saints boss will stick with the 5-3-2 formation that brought their first clean sheet on the road since February.
Their hosts Midtjylland have injury worries of their own; young wing wonder Pione Sisto came off injured in the 1-1 draw at St Mary’s and sat out the Wolves’ 1-1 draw with Esbjerg on the weekend. Rilwan Hassan may deputise for the Danish U21 star.
Predicted line-ups
Southampton (5-3-2)- Stekelenburg, Cedric Caulker Fonte Yoshida Targett, Davis Ward-Prowse Romeu, Pellè Rodriguez
Midtjylland (4-1-4-1) Dahlin, Rømer Sviatchenko Lauridsen Hansen, Sparv, Royer Poulsen Andersson Sisto, Pusic.
Key players
If he overcomes a fitness test, Southampton’s hopes will be on the shoulders of Sadio Mané with his pace a real weapon away from home. If he fails, Jay Rodriguez will hope to score again against the Danish champions, having netted his first goal for 16 months from the spot in the first leg.
Tim Sparv scored the shock away goal for Midtjylland on his return to St Mary’s having spent time on the South Coast in the lauded Saints academy, but his main job will be making sure Saints don’t score, and will sit just in front of the defence.