A Messi-less Argentina was crushed 6-1 by Spain as Real Madrid attacking midfielder Francisco "Isco" Alarcon scored his first career International hhat-trick As the five-time ballon d'Or winner watched from the stands at the Wanda Metropolitano Stadium in Madrid, Spain dealt Argentina a humbling loss in the last match before their coaches pick their squads for this summer's World Cup.
Spain remained undefeated in 18 matches under Julen Lopetegui and strengthened its credentials as a favorite for the title in Russia.
Lopetegui said he congratulated his players, but reminded them that this was only a preparation match.
"The reality is that nothing has started yet. We will begin the World Cup with zero points," Lopetegui said.
Jorge Sampaoli, however, will face more doubts about Argentina's chances to finally win a World Cup title with Messi after seeing his supporting cast so thoroughly outclassed.
Diego Costa, Thiago Alcantara and half-time substitute Iago Aspas also scored for Spain. Nicolas Otamendi scored Argentina's goal that made it 2-1 at halftime.
A minor leg problem kept Messi from playing in Argentina's 2-0 win over Italy in Manchester, England, on Friday.
Sampaoli had said on Monday that his star player was better and that he expected him to play against Spain, but he left him out of his squad come match time.
Sampaoli said after the match that if the game had not been a friendly Messi would have played.
"Leo had been training well with us this week but he was still bothered by his leg, and after the last practice session he felt that fatigue," Sampaoli said. "Obviously, we noticed his absence."
The match was intense and ended in a brief scuffle after hard foul by Argentina's Cristian Pavon to cut down Jorge "Koke" Resurreccion.
Gonzalo Higuain was in Argentina's squad for the first time since June, but did little to improve his chances of being on Sampaoli's World Cup list when he tapped a cross by Maximiliano Meza wide from close range eight minutes into the match.
Costa struck first for Spain after Andres Iniesta recovered the ball near Argentina's area and Marco Asensio slipped a ball for the Atletico Madrid striker to bundle past goalkeeper Sergio Romero.
Both Costa and Romero briefly writhed on the turf following their collision, and Romero needed to be substituted 10 minutes later. He was replaced by Willy Caballero.
Asensio again undid the defense when he squared a pass from the right flank to meet Isco's run in from the left side. Isco used one touch of his right boot to slot the ball home.
Otamendi pulled one back when he headed a corner kick through the arms of goalie David De Gea in the 37th.
The second half, however, was all Spain.
Isco fired in a pass by Aspas in the 52nd after the striker deftly controlled a long pass by Iniesta to break behind the defense.
Thiago drilled in Spain's fourth in the 55th when Isco crossed for Aspas, whose bobbled control fell right into the path of the Bayern Munich midfielder.
Argentina's defense was caught off-guard by De Gea's long ball right down the pitch that Aspas ran onto and stroked past the on-rushing Caballero in the 73rd.
Isco then intercepted a pass by Otamendi and combined with Aspas to get his third goal in the 75th.
Marco Alonso and Dani Parejo debuted for Spain late.
VAR HELPS ITALY SAVE GRACE
World Cup-bound England conceded its first goal in more than 10 hours after a video review allowed Lorenzo Insigne to equalize for Italy and claim a 1-1 draw at Wembley Stadium on Tuesday.
German referee Deniz Aytekin went over to a pitch-side monitor to review James Tarkowski's challenge on Federico Chiesa and decided to award a spot kick, which Insigne converted in the 87th minute to cancel out Jamie Vardy's opener.
"I stood on his foot," Tarkowski said, "but I didn't think a lot of it."
The close call on the penalty came in front of representatives from more than 65 soccer organizations who attended the game as part of a video assistant referee workshop.
"I'm glad it's not the World Cup," England coach Gareth Southgate said. "I don't think it's clear and obvious. It's one you can debate forever. (Tarkowski) looks like he stands on him but I think that's in the motion of running and he looks like he was on his way down anyway."
England had been set for a second successive victory after a victory on Friday over the Netherlands, which like Italy, has not qualified for the World Cup.
Vardy put England in front in the 26th minute after Raheem Sterling was bundled to the turf by Marco Parolo and Jesse Lingard's quickly-taken free kick fed the striker to score.
It was England's last game before Southgate names his provisional squad in May to take to Russia for the World Cup.
"I thought the first five minutes was very sloppy," Southgate said. "After that we settled into the game. We probably created more chances than we've done in a lot of matches."