The two sides were level on points ahead of their Group G game after six games as the race to Russia in 2018 becomes intense, but there was something else at stake in Saturday's encounter.
The Azzurri had not suffered a loss in the preliminary European Championship and World Cup phase since a France team consisting of Thierry Henry, Claude Makelele and Patrick Vieira beat them 3-1 in 2006.
Italy's team the last time they lost a World Cup or Euro qualifier... 11 years ago! pic.twitter.com/pc3FMOfDF9— Goal (@goal) September 2, 2017
Meanwhile, 59 games had gone by since the last time Spain were beaten in World Cup qualifiers - a 1-0 defeat to a Peter Schmeichel and Michael Laudrup-led Denmark in 1993.
The two sides failed to get the better of each other when they met in Italy in the previous fixture, but there was no share of the spoils this time around.
A double from Isco and one goal from Alvaro Morata ensured that Italy's run stopped at 56 games. Interestingly, Gianluigi Buffon and Andrea Barzagli were the only Italy players to feature in both defeats.
Spain, however, are 24 years and counting!