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Their first south coast derby with Brighton will take place at the Amex Stadium on December 5, with the return fixture at St Mary's on March 13.
The festive period looks tricky for the Saints with games against Arsenal, Manchester City and Liverpool between December 15 and January 2, as well as a Boxing Day trip to Fulham and a home game against West Ham on December 28.
In their final five games of the season, Southampton will take on Leicester, Liverpool, Fulham and Leeds, before a trip to West Ham on the last day.
Check out Southampton's full Premier League schedule for 2020-21 below.