A draw will secure Portugal a place in the Nations League finals with Spain making the hop over the Iberian border.
A surprise slip-up against Switzerland means Luis Enrique’s side must win to have any hope of topping Group A2.
The first meeting between the pair in Seville ended one apiece in June.
Joao Cancelo could return to Fernando Santos’ side while Enrique may well opt to make alterations after struggling to make possession dominance tell against the Swiss.
Here’s everything you need to know ahead of the fixture.
When and where is it?
Portugal vs Spain is due to kick-off at 7.45pm BST on Tuesday 27 September at the Estádio Municipal de Braga in Braga, Portugal.
How can I watch it?
Viewers in the United Kingdom can watch the game live on BoxNation, with coverage due to begin at 7.35pm BST. Premier Sports subscribers can stream the game via the Premier Player.
Portugal XI: Costa; Cancelo, Danilo, Dias, Mendes; Neves, Carvalho, Fernandes; Bernardo, Ronaldo, Jota.
Spain XI: Simón; Carvajal, Guillamón, P Torres, Gayà; Koke, Rodri, Soler; F Torres, Morata, Sarabia
Portugal win 11/8
Spain win 12/5
It feels unlikely that this will be a particularly open encounter, with a place in the Nations League finals on the line and the World Cup looming into view. A draw would suit Portugal, who are tight defensively. Portugal 1-1 Spain