Southampton take a 3-0 lead into GelreDome, the home of Vitesse. It is the first time they will have travelled to Holland for a competitive fixture.
Jordy Clasie limped off during the second half of the first leg and the extent of the midfielder’s hamstring injury is not yet known, but the Dutchman did not travel with the squad.
Jay Rodriguez could make his first appearance in 16 months and on-loan Steven Caulker is in line for his debut in Arnhem, although Ryan Bertrand, Gaston Ramirez, Florin Gardos and Fraser Forster are absent.
English youngsters Lewis Baker and Izzy Brown, both on loan from Chelsea, are expected to feature for the home team as they look to overturn the deficit.
Despite Southampton’s lead, manager Ronald Koeman has demanded concentration from his players. Vitesse was the first club Koeman took charge of as a head coach.
He said: “I hope [it will be] a good game and for sure a game we will start with the same intensity as we did last week.
“It’s a comfortable result, but only after 90 minutes. Football is sometimes strange and, if we don’t start with enough concentration and don’t play with the same intensity of pressing the opponent then it’s possible you get a difficult evening.
“If we play on our level with the same concentration and intensity, the quality makes a difference.”
Vitesse have not scored in any of their five games against Premier League clubs, conceding eight goals in total.
The match in Holland kicks off at 19.00 BST.