Having run out 1-0 winners when the sides last met three years ago, they are 11/8 (2.38) favourites with bet365 to come out on top once again at the Estadio da Luz.
Just one of the last 14 encounters between this pair has resulted in a draw, although you can get odds of 21/10 (3.10) on them cancelling each other out in this one.
Cristiano Ronaldo is a headline omission from the Selecao squad as he concentrates on settling in at Juventus, with a number of other big names missing as part of a post-World Cup shake-up.
After an anonymous display against Poland, Mario Balotelli could be dropped to the bench in favour of Andrea Belotti or Ciro Immobile.
Goals at both ends
Despite Ronaldo’s absence, the home team should be feeling confident of hitting the back of the net against a visiting defence that has kept just one clean sheet in the last eight fixtures.
All in all, odds of 11/10 (2.10) appear generous on both teams scoring for Italy’s sixth match in a row, as well as a fifth in six for Portugal.
Odds correct at the time of writing. Please gamble responsibly.