The pair are fighting to preserve their place in the top tier of English football, with the Hammers in 17th and the Saints one place below.
Saturday's hosts have been beaten in four of their last five league fixtures, but David Moyes’ men will fancy their chances of winning here as Mark Hughes' men have recorded just one win in their last 17.
West Ham have lost just two of their previous 10 matches at London Stadium and bet365 go 17/10 (2.70) that they pick up three precious points on Saturday.
Southampton have an FA Cup semi-final to look forward to but Premier League survival is the Saints’ primary concern.
Hughes paired Guido Carrillo and Manolo Gabbiadini in attack against the Latics last time out and the former Stoke City boss could start with that pair again here.
Manuel Lanzini faces a race to be fit after picking up a knock on international duty with Argentina, whilst Edimilson Fernandes (ankle) could play for the first time since early December.
Goals at both ends?
Saints have scored in all but one of their seven away matches in 2018, while West Ham have scored in 12 of their last 13 matches in this competition.
Preview and predictions
The Hammers are a team in trouble, while the Saints will have been encouraged by their winning display against Wigan last time out.
Hughes has never suffered relegation as a manager and his side are good value at 8/5 (2.60) to heap yet more misery upon Moyes and his players with a win this weekend.
Odds correct at time of writing. Please gamble responsibly.