Isco scored twice as a scintillating Spain beat Italy at the Bernabeu to take a huge step towards qualifying for the World Cup from Group G.
The hosts started without a striker, but did not need one with the Real Madrid playmaker curling home a free-kick and then smashing in a second.
Chelsea's Alvaro Morata came on to add a third from Sergio Ramos' cross.
Italy, who trail Spain by three points with a much worse goal difference, are likely to be in the play-offs.
The Azzurri had not lost a qualifier for a major tournament since 2006 World Cup qualification.
Only the winners of each group qualify directly for Russia, with the eight best ranked second-placed teams playing off.
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