The Iberian nation started their qualification process with back-to-back home draws against Ukraine and Serbia, before beating Serbia and Lithuania away in their last two fixtures.
Portugal's next match after this one is away to Ukraine on Monday night, and Santos will be desperate for his side to enter the key fixture off the back of a victory.
Here, Sports Mole looks at how the home side could line up in Lisbon.
It seems likely that Santos will keep with the bulk of the team that started the 5-1 win over Lithuania last time out, where Cristiano Ronaldo scored four times during a stunning performance.
Further back, there are not expected to be any surprises with Bruno Fernandes starting in central midfield alongside Ruben Neves and William Carvalho, who will provide the protection for his back four.
Jose Fonte and Ruben Dias should also continue in central defence, although there might be a change at right-back with Nelson Semedo back in the squad. As a result, Joao Cancelo could drop out of the XI, although Santos has the option of switching the Manchester City defender to left-back.