Pundit Mark Lawrenson has predicted in his weekly BBC column that Tottenham will lose 2-1 to Southampton this weekend.
Saints fans will therefore be looking to give the Argentine a miserable return, but have stumbled in recent weeks, losing twice in their last three games - including the 2-1 loss to Stoke City last weekend.
Tottenham on the other hand won last weekend, defeating Newcastle 3-1 thanks to goals from Nacer Chadli, Christian Eriksen and Harry Kane.
Their hopes of a top four finish look unlikely, but Pochettino will know that all they can do is keep winning in order to keep the pressure on Liverpool and Manchester City.
The corresponding fixture between the two sides this season ended in a 1-0 win for Tottenham, and now Pochettino will hope to make it a league double for Spurs against his former employers.
However, Lawrenson predicts that Spurs will lose 2-1 this weekend, believing that the Southampton faithful will raw their team on against ex-manager Pochettino.
"Tottenham had a good win at Newcastle on Sunday but the Magpies are everyone's favourite team to play at the moment so you cannot read too much into that. Southampton lost to Stoke last time out and it seems chances and goals are still hard to come by for them," said Lawrenson.
"But Mauricio Pochettino is back at St Mary's for the first time since leaving Saints for Spurs last summer. His new team are a point and a place above his old one and I think the return of their former manager will get the crowd going. There should be a great atmosphere, and I fancy a home win," he added.