It will be up to struggling Aston Villa to try and stop high-flying Southampton in their tracks, with the Villans desperate to end the barren run of results.
Meanwhile, the Saints are searching for their fifth victory on the bounce and an opportunity to cement their place in Premiership top 4.
Buoyed by some impressive displays from last season, Aston Villa enjoyed a near perfect start to the new campaign, taking ten points from their first four league fixtures.
However, the Villans then paid the price for a difficult run of fixtures and went on to suffer six defeats in a row, scoring just one goal in the process.
Their back line looked much better against West Ham ahead of the international break, with the goalless draw at Boleyn Ground ending the losing streak.
Aston Villa now hope to record the first win after over two months, but the hosts are no less than 5.25 (16/5) to defeat red-hot Southampton.
Injury problems continue to mount for Paul Lambert, seeing as how key players Fabian Delph and Ron Vlaar are both out injured.
Philippe Senderos, Nathan Baker and Libor Kozak are sidelined as well, but Alan Hutton should return from an ankle problem. Christian Benteke is suspended.
Probable starting line-up (4-3-3): Guzan – Hutton, Okore, Clark, Cissokho – Cleverley, Westwood, Sanchez – N’Zogbia, Agbonlahor, Weimann.
Southampton are enjoying their best ever start to a Premier League campaign and the only question is whether they can keep the rich vein of form for much longer.
The Saints have been absolutely brilliant in the opening exchanges, taking 25 points from 11 league matches, and they will remain in second position regardless of the outcome of the Aston Villa clash.
However, seeing as how they already have a six-point advantage over fifth-placed Newcastle, Southampton will be out to further boost their top 4 hopes, with away win paying 1.80 (4/5).
Having won last four league fixtures, the Saints clearly go into the match at Villa Park brimming with confidence and no doubt they are in much better shape than the opposition.
Boss Ronald Koeman will have Dusan Tadic and Morgan Schneiderlin back after they suffered minor injuries while on international duty.
Steven Davis faces a fitness test, but James Ward-Prowse and Jay Rodriguez remain long-term casualties for the Saints.
Probable starting line-up (4-3-3): Forster – Clyne, Fonte, Alderweireld, Bertrand – Davis, Wanyama, Schneiderlin – Tadic, Pelle, Mane.