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Everton have a dismal record at St. Mary's, having not scored in their last three visits - losing two of those - and only recording two victories away from home against Southampton.
The Saints' foes also draw 2-2 in their Premier League opener against new boys Watford, so they will also be raring to go as the Toffees look to record their first win of the season.
Everton boss Roberto Martinez said:"I think the last two visits to Southampton have been really tough for different reasons," the 42 year-old told reporters ahead of the game.
"I don't think it's been difficult for just football aspects. Things that could go wrong have gone wrong. Two years ago we had two own goals very early.
"In 22 years we've only had two wins so it's not just in the last two seasons. In the last six visits we have had three defeats and three draws.
"Historically it's a tough place for us, but it's an extra challenge that we want to embrace."
Oriol Romeu may make his Saints debut as it was confirmed that Jordy Clasie will be out of action through injury. New loanee Steven Caulker is also unavailable.
Saints boss Ronald Koeman will make his return to the St. Mary's sidelines having missed the away trip at Newcastle following Achilles tendon surgery.
Meanwhile, Everton are missing Leighton Baines. But, Martinez will be able to select the likes of Kevin Mirallas, Muhamed Besic, Aiden McGeady and Gerard Deulofeu as they all recovered from niggling injuries.