In 2010, the hosts were led to Champions League glory by Jose Mourinho, while the Saints had just won the Johnstone’s Paint Trophy whilst lying 7th in League One, the third tier of English football.
Sofiane Boufal could make his long awaited debut for Saints tonight after his £16m move in the summer, but hasn’t yet seen any game time due to a knee injury.
The attacking midfielder was the record signing for Saints, and the faithful are eagerly awaiting to see him don the red and white stripes.
Other summer signing Nathan Redmond, as well as defensive duo Cedric Soares and Matty Targett have not travelled to Italy for unknown circumstances.
Claude Puel's outfit are unbeaten in all competitions after a slow start to the campaign and have four points from the first two Europa League games.
The match at the San Siro will be the first meeting between the two clubs and with the Italian giants struggling of late, Saints can produce a performance and create a historical memory for the club.
Inter have lost both games in Group K, at home to Hapoel Beer Sheeva and away to Sparta Prauge and have lost a three in a row in domestic competition and sit astoundingly 11th in Serie A.
The Italian Giants have been in turmoil from day one this season, losing manager Roberto Mancini just two weeks before kick off in the new season, limits on the Europa League squad and their own captain going to war with their fans.
Frank De Boer, who was linked with the Saints job after the departation of Ronald Koeman, has a full strength squad to choose from but will most likely not risk Mauricio Icardi, who is unsure whether he will play for the club again.
Icardi slated the “Ultras” in his book and the fans did not take it well turning up at his front door to confront the one time adored striker but Police calmed the incident, however, it is unlikely that Internazionale fans will forget it in a hurry.
If Inter Milan don’t get a result tonight then they face an impossible task to qualify out the group and will be on the verge of elimination with Southampton in prime position to finish top.