- Aston Villa v Blackburn Rovers: As it happened
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The former Arsenal star restored Villa's lead after Ciaran Clark's opener had been cancelled out by Rovers substitute Nikola Kalinic.
Nathan Delfouneso doubled Villa's lead and even a red card after 62 minutes for defender Nathan Baker, after a challenge on Junior Hoilett, failed to halt their progress.
Villa, who knocked Blackburn out of the Carling Cup and FA Cup last season, deserved their place in the last 16 despite manager Gerard Houllier making six changes.
Rovers suffered a setback after only 10 minutes when Roque Santa Cruz limped out of the action and was replaced by Kalinic. Then a minute later Villa went ahead through Clark's fourth goal of the campaign.
Barry Bannan's corner was met perfectly by the central defender, whose header powered past Paul Robinson.
Gabriel Agbonlahor, operating in a wide role, showed his pace before setting up a chance for Delfouneso whose volley was only just too high.
Blackburn threatened for the first time when former Rovers goalkeeper Brad Friedel beat out a shot from a narrow angle by Hoilett.
Then after 18 minutes Rovers drew level through Kalinic. Delfouneso lost possession to Morten Gamst Pedersen who picked out the run of Michel Salgado, and the Spanish full-back's low cross was turned home by the Croatian.
Villa were dominating possession and Bannan was only just off-target with a 30-yard drive, and after 35 minutes Pires restored Villa's lead with his first goal for the West Midlands club.
Grant Hanley and Martin Olsson only half-cleared the ball and the former Arsenal player struck the ball perfectly on the half-volley from 15 yards out into the roof of the net.
Blackburn's reponse was immediate and Friedel produced a fine save to finger-tip away a header from Christopher Samba.
But Villa made it 3-1 three minutes before half-time when Delfouneso headed home a cross from teenager Baker.
The game was flowing from end to end and Olsson crashed a shot against the crossbar.
Houllier made a half-time substitution with Stewart Downing replacing Agbonlahor. Villa forced three successive corners and, from the third of them, Baker headed just wide at the far post from a Pires centre.
The on-loan Kyle Walker made a powerful 50-yard run and saw his rising shot blocked by Hanley, and Downing's centre picked out Delfouneso at the near post but he could only deflect the ball wide.
Blackburn should have reduced the arrears when Keith Andrews headed wide from eight yards out from Hoilett's centre.
Villa were reduced to 10 men after 62 minutes when Baker was given a straight red card by referee Lee Probert for a challenge on Hoilett.
Blackburn tried to make the most of their numerical advantage and Hoilett shot over from 10 yards out.
Jason Roberts carved out a chance for himself but James Collins made a vital tackle as he prepared to shoot, before Downing had two chances to wrap up the game for Villa.
First Robinson parried his shot after a 60-yard run and then blocked his close-range header.