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The RBS 6 Nations record try-scorer will win his 129th cap in Dublin, moving him clear of Ronan O'Gara, who remains the Championship's all-time points scorer.
But while O'Driscoll is an RBS 6 Nations veteran, making his first appearance in the competition in the year that five became six, Joe Schmidt is the only head coach making his Championship bow.
Hopes are high in Ireland however, such were Schmidt's feats with Leinster and now that the dust has settled on their heart-breaking 24-22 defeat to New Zealand in the autumn, the Kiwi coach can take plenty of positives from the performance.
He is without Sean O'Brien, man of the match against the All Blacks, but in-form Ulster flanker Chris Henry fills in and a stomach bug has ruled out Gordon D'Arcy - O'Driscoll's partner-in-crime for so long.
There is also a lengthy list of absent wingers with Tommy Bowe, Simon Zebo and Luke Fitzgerald not available but back comes Andrew Trimble to the fold, while the promising Luke Marshall fills in for D'Arcy.
"Gordon's stomach bug was the sole selection criteria, really," Schmidt said. "Luke Marshall has played really well in some big games.
"He played in the RBS 6 Nations last year and played very well against Scotland.
"I thought he played well against Australia in the autumn too. He made a defensive error at one stage, but he's learning all the time. He's working hard at everything we're trying to do.
"He's between Jonny Sexton and Brian O'Driscoll, so experience-wise, he's a bit inexperienced but either side of him he has two players who can help him navigate his way through the game.
"Andrew brings a bit of size, up against Lamont and Maitland.
"We don't have too many men of that size and stature, so Andrew is a good contrast for us."
Scotland meanwhile, are going in search of a first win on the opening weekend since France left Murrayfield empty-handed in 2006 but are boosted by the return to international action of Stuart Hogg and Tim Swinson.
Both missed the autumn campaign but both have impressed for Scotland of late - Hogg in last year's Championship and Swinson in South Africa over the summer.
Influential centre Matt Scott, who picked up a hand injury in Scotland's opening autumn clash with Japan, is fit enough only for the bench but interim head coach Scott Johnson believes Hogg's return to form can be the catalyst for a first win in Dublin since 2010.
"Hoggy is a senior player now for being such a young lad and I'm glad he's with us, and not the other sides," said Johnson.
"I'm glad also that his form has started to turn. Some people take a while after a Lions tour, especially the young ones, to get back in the swing of things.
"Stuart has taken a wee while, probably longer than he wanted, to find his feet. He's had some time off in the autumn with the injury and has come back to some form lately. He's buoyed by that and so are we."
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