It's a teatime start for Saints in what is sure to be a memorable occasion for their travelling contingent in the San Siro.
Southampton's Charlie Austin celebrates
Southampton have come a long way in just six years. Whereas in 2010 they spent their October facing the likes of Oldham Athletic and Tranmere Rovers in League One, on Thursday evening they will run out at the San Siro to face Inter Milan.
Around 7,000 Saints fans are expected to make the journey to Italy for one of the finest occasions in the club's history, and they should be more than a match for their illustrious opponents on the pitch; Inter are not the force they were and have lost their last three games in all competitions.
Burnley's Sam Vokes in action with Southampton's Jose Fonte
The Key Battle - Mauro Icardi vs Jose Fonte
It is doubtful whether Inter striker Icardi will play given his well-publicised spat with the club's ultras; Frank de Boer gave the frontman a start at the weekend but he missed a penalty in Inter's defeat against Cagliari.
Despite the ongoing tensions, the Argentine is still a gifted striker and Fonte will have to stay alert to keep him quiet.
Mauro Icardi at Inter
These two sides have never met before, with Inter's last match against Premier League opposition coming against Tottenham in 2013.
After being beaten 3-0 at White Hart Lane in the first leg of the Round of 16 tie, Inter won the second leg 4-1 at the San Siro and were knocked out on away goals.
Recent form – most recent last:
Inter - WWDLLL
Southampton - WWWDDW
Who’s the ref?
Lithuanian official Gediminas Mazeika will be in charge at the San Siro. He showed seven yellow cards in his only Europa League game so far this season, which came in Qabala's 3-2 defeat to Mainz.
General view of the San Siro
What time is kick off?
The game begins at 6pm.
Where can I watch it?
BT Sport 3 are providing live coverage from the San Siro, with the build-up getting underway at 5.30pm.
Inter - 13/10
Draw - 12/5