The two sides have been among the strongest at Euro 2020 too and will do battle in the semi-final on Tuesday at Wembley Stadium for a place against either England or Denmark in Sunday's final.
Spain needed penalties to get past Switzerland in the quarter-finals last week, while Italy beat Belgium 2-1 in Munich to qualify for the last four. But how do La Roja and the Azzurri stack up against each other in their meetings in this competition?
Here, Sportsmail takes a look at the Spain-Italy rivalry as they get set for a fourth consecutive Euros knockout clash...
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Italy face Spain for a place in Sunday's Euro 2020 final in the latest encounter of their rivalry
Luis Enrique's men needed penalties to beat Switzerland while the Azzuri overcame Belgium
Euro 2016 - Italy 2-0 Spain - round of 16
Spain had reigned as European champions for eight years ahead of their meeting against Italy in Paris five years ago.
But after recent success against the Azzurri and in the tournament as a whole, La Roja's domination on the continent came to an end against a tactically superior Italy side under Antonio Conte.
Giorgio Chiellini opened the scoring, scrappily bundling home from close range after David de Gea - who otherwise had an outstanding game - had failed to push Eder free-kick's away from danger.
Graziano Pelle (right) scored in injury time to secure a win for Antonio Conte as the latter delivered a tactical masterclassInsurance Loans Mortgage Attorney Credit Lawyer
Spain only managed to exert some pressure in the latter stages of the match but came up against the might of Gianluigi Buffon.
The Juventus legend first saved from Andres Iniesta and then twice from Gerard Pique before the hammerblow for Spain arrived.
Former Southampton striker Graziano Pelle rang the death knell, volleying home from eight yards out in injury time after Matteo Darmian's cross fell nicely for him despite Spain's best efforts to clear.
The result not only saw Antonio Conte's men correct what was starting to become an unwanted record against Spain, but it also proved to be Vicente del Bosque's final game in charge of La Roja, leaving three days later after his deal expired.
Conte's final game in charge of Italy came a game later when they suffered a quarter-final defeat by Germany on penalties, with the Italian going on to join Chelsea and win the Premier League in his first season at Stamford Bridge.
It was to be Vicente del Bosque's final game in charge of La Roja, leaving his role three days later
Euro 2012 - Spain 4-0 Italy - final
As brilliant as Italy would be with their tactics in wing-backs Mattia de Sciglio and Alessandro Florenzi four years later, Spain were equally as convincing with their passing game in the Euro 2012 final in Kyiv.
The duo had met earlier in the tournament during the group stages, when Cesc Fabregas - playing the false nine role - had earned Spain a 1-1 draw after Antonio Di Natale's opener in Gdansk. But there was to be no close contest in the scoreline just a few weeks later.
The Italians were in the game for large portions but were ultimately put to the sword by an incredible exhibition of pass-and-move football which was synonymous with Spain's crop of players at the time.
One such spellbinding passing exchange saw ex-Manchester City midfielder David Silva head his country into the lead from an inch-perfect Fabregas delivery.
Jordi Alba scored a memorable goal in the Euro 2012 final as Spain beat the Italians in Kyiv
The Spaniards therefore added a second straight Euros crown to their World Cup 2010 title
Jordi Alba - who captained Spain in the group stages at Euro 2020 before the return of Sergio Busquets from Covid - then added a second after a surging run and a similarly remarkable pass from Xavi.
Cesare Prandelli had to act and brought on Antonio Di Natale for his namesake Cassono, and the former Udinese man almost brought Italy back into the game but for a fine save from Iker Casillas.
However, the die was cast when a hamstring injury to fellow substitute Thiago Motta saw Prandelli's men reduced to 10 and Spain, in ruthless mood, took advantage through Fernando Torres, coolly slotting home another slick Xavi pass for a third.
The former Liverpool and Chelsea striker then turned unselfish provider, squaring for an open Juan Mata to steer home a fourth. A second straight Euros