The Irish are smarting at having lost their last three meetings against the Grand Slam champions, the most high profile of which was the 2011 World Cup quarter-final defeat in Wellington.
That clash sandwiched two controversial Six Nations games that left Ireland nursing a sense or grievance that continues to fester.
"Wales has become a championship-defining match. You can't win a Grand Slam on the first day, but you can lose one if you don't make a good start," O'Brien said.
"Things didn't go our way last year, which was unfortunate because we played so well at times during the game.
"But we didn't play for the full 80 minutes, which is what we're looking to do this time.
"Wales may have lost seven in a row, but I don't think they'll be nervous at all.
"It's obviously a massive game for us. Wales are very tough opposition. The set-piece and breakdown will be massive."
Ireland's build-up to the game began with headlines over fly-half Jonathan Sexton's departure for France at the end of the season.
Sexton will be the nation's first Test star to head for the Top 14 and his Leinster team-mate O'Brien, who has been restored to Ireland's back row after missing the autumn with a hip injury, will listen to similar offers when his contract with the Irish Rugby Football Union expires next year.
"It's Jonny's decision and I'd back him wherever he goes. He's a good friend who has done a lot for Leinster since being in the academy," he said.
"We're a big club. People come and go and I'm sure it will happen again at some stage.
"I don't think there are too many lads who will follow suit. People are happy where they are at the moment as the provinces are doing well.
"The IRFU look after players pretty well and that's a factor in any decision.
"When the time comes if clubs are after you, you're going to take into consideration what's on offer.
"You've only so long in the game and you have to look after yourself. They're tough decisions to make, but you live and die by them."
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