The last time Spain had lost by the same margin was in a 6-2 defeat against Scotland in Madrid in 1963.
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Spain lost 4-1 to Argentina in a friendly in September, but while that side featured several second string players, the starting line up against Portugal was near full-strength.
"We have to accept the defeat. We couldn't have played any worse. They were very effective on the counter-attack and did us a lot of damage," coach Vicente Del Bosque told Spanish TV.
"Nobody likes to lose. It was an important match for us but it wasn't our day," he added.
In contrast, the Portuguese put on their best performance in some time and are improving under coach Paulo Bento, who took charge in September after Carlos Queiroz was sacked.
"We wanted to win, but could never have predicted a result like this against a team with Spain's dimension. The way we played had a lot of positives. The win does not bring points, but it does earn us prestige," Bento told reporters.
The coach has revived Portugal's Euro 2012 hopes with two wins over Denmark and Iceland in October after the side had made a dismal start prior to his appointment, but he was eager not to get carried away with the rout against Spain.
"I think our quality in the victory is not in question. But we were not the worst team in the world when we were in an tough spot, and these wins, including this one, do not make us the best one either," Bento added.
Portugal were strong from the start and did not show any of the caution that marked their 1-0 defeat in the second round of the World Cup to the same opponents.
Nani had the first chance but his drive from outside the box flew wide of the right post. The winger also put Postiga through on 20 minutes only for his chip to be blocked by Casillas.
The game, held to promote the countries' joint bid to host the 2018 World Cup, was at times an intense affair, with Busquets and Ronaldo picking up yellow cards for challenges on each other.
Midfielders Raul Meireiles and Moutinho worked tirelessly, preventing Xavi and Iniesta from deploying their trademark "tiki-taka" one-touch style, with Spain's only real chance in the first half a David Silva header that went wide on 31 minutes.
DESERVED LEAD
Portugal took a deserved lead just before half-time when Cristiano Ronaldo beat Sergio Busquets on the left and sent a powerful drive towards Iker Casillas which the Spain keeper could only block. The ball fell for Carlos Martins to fire in from near the spot.
The hosts added their second five minutes after the break when Joao Moutinho and Nani combined to feed striker Postiga, whose goalbound backheel was helped in by Sergio Ramos's desperate clearance.
Postiga netted again with a s
