Italy go 4-2-4 with Lorenzo Insigne, Andrea Belotti and Marco Verratti, while Spain use David Silva or Marco Asensio as a False 9 in the World Cup qualifier.
It kicks off at the Bernabeu in Madrid at 19.45 UK time (18.45 GMT).
These sides are locked together at the top of Group G, but only the winners go directly into the tournament in Russia, with the runners-up needing a play-off.
Goal difference is currently in Spain’s favour, so realistically the Azzurri have to win on Spanish soil – something they haven’t done since 1949.
With Giorgio Chiellini suffering a calf strain and Roberto Gagliardini suspended, Coach Giampiero Ventura has opted to go all-out attack with an audacious 4-2-4 system.
It means Daniele De Rossi and Verratti hold the fort in midfield with Insigne, Belotti, Ciro Immobile and Antonio Candreva all starting together.
Leonardo Spinazzola is a shock choice for left-back, as he hasn’t played at all for Atalanta this season due to a contract dispute when he tried to force through a Juventus move.
With Chiellini out and Alessio Romagnoli not fully fit either, Andrea Barzagli partners Leonardo Bonucci.
Spain are without Diego Costa, but new Chelsea buy Alvaro Morata is left on the bench in favour of a False 9 formation.
Coach Julen Lopetegui believes this is the way to get the best out of on form Real Madrid talent Marco Asensio, joining Isco and David Silva in a 4-3-3 formation.
The UEFA teamsheet suggests it is a 4-2-3-1 with Silva, Andres Iniesta and Asensio fanning out behind Isco.
Koke gets the nod rather than Thiago Alcantara in midfield, joined by Sergio Busquets and Andres Iniesta.
Lopetegui is unbeaten on the Spanish bench, earning seven victories and three draws.
The referee is Bjorn Kuipers and Spain have lost all three matches when the Swede was officiating.
Spain: De Gea; Carvajal, Ramos, Pique, Jordi Alba; Busquets, Koke; Silva, Iniesta, Asensio; Isco
Spain bench: Reina, Arrizabalaga, Azpilicueta, Bartra, Nacho, Thiago Alcantara, Saul Niguez, Deulofeu, Morata, Pedro, Villa, Aspas
Italy: Buffon; Darmian, Barzagli, Bonucci, Spinazzola; De Rossi, Verratti; Candreva, Belotti, Immobile, Insigne
Italy bench: Donnarumma, Perin, Astori, Rugani, Conti, D’Ambrosio, Parolo, Pellegrini, Bernardeschi, El Shaarawy, Eder, Gabbiadini