The Ospreys produced a scintillating second-half performance with a convincing bonus-point victory at the Liberty Stadium.
James Hook contributed 22 out of 27 unanswered points in 25 second-half minutes after a tight opening period.
Shane Williams opened the scoring after three minutes with an unconverted try, with Ben Blair replying with a penalty.
But two tries from Hook and another from Tommy Bowe ensured Aled Brew's try was just consolation for the Blues.
With the two regions in the middle of a tough brief of three games in eight days there were changes on both sides.
The Ospreys made seven from the team which won at Connacht and the Blues named nine changes following their 16-16 draw with Leinster.
After Williams' opening try, the Ospreys had to show some well-organised defence to stop three concerted Blues attacks into their 22.
The Blues were eventually rewarded for their territorial dominance with a penalty from Blair on 39 minutes, after a ruck offence from Ospreys lock Alun Wyn Jones, to make it 5-3 at the interval.
An impressive run by Filo Tiatia set up good territory from where Hook landed a 48th-minute penalty goal.
An 8-3 lead became 11-3 three minutes later as Hook found his range again as the Blues strayed offside.
Hook completed 13 unanswered points in five minutes when he was on hand to run in and convert the Ospreys' second try after a brilliant run by Lee Byrne as the home side's lead increased to 18-3.
That became 25-3 when a Hook cross-kick was kicked ahead and picked up by Bowe to go over for try number three, converted by Hook.
Those 20 points had come in just nine minutes.
And Hook was put across for his second try by new Ospreys scrum-half signing Jamie Nutbrown on 72 minutes to register a bonus point.
In injury time Brew crossed for a converted try to give the score-line some respectability as far as the Blues were concerned.
Ospreys wing Shane Williams:
"We made hard work of it at the start.
"We scored that early try and we felt we had the momentum, but it wasn't to be in the first half.
"The second-half performance was one of the best I've seen."
Blues coach Dai Young:
"We were well in the game at half-time after a disastrous start in the first three minutes.
"I thought we worked hard to get back into the game and was quite pleased at half-time.
"But against a team of this quality, you can't give away silly tries."
Ospreys: Byrne, Bowe, Parker, A. Bishop, Williams, Hook, Wells, R. Jones, Tandy, Tiatia, Evans, Wyn-Jones, A. Jones, Bennett, D. Jones. Replacements: Walker for A. Bishop (58), Nutbrown for Wells (67), Smith for Tiatia (73), Gough for Wyn-Jones (73), James for A. Jones (73), Shervington for Bennett (77). Not Used: Owen.
Cardiff Blues: Blair, Mustoe, J. Robinson, J. Roberts, Brew, Sweeney, Allinson, A. Powell, Sowden-Taylor, White, Morgan, Davies, G. Powell, T. Thomas, Filise. Replacements: Shanklin for J. Roberts (41), Molitika for White (73), Tito for Davies (67), Jenkins for Filise (46). Not Used: G. Williams, Spice, N. Robinson.
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