Connacht's Robbie Henshaw has been withdrawn from Ireland's tour to Argentina due to a hand ligament injury.
Henshaw sustained the injury earlier in the season but it had not limited his ability to train or play, according to an IRFU statement.
He exacerbated the injury in training this week and received further specialist advice that recommended surgical repair of the damaged ligaments should not be delayed further.
The 20-year-old has been widely tipped to succeed the retired O'Driscoll in Ireland's midfield, but will now miss out on the first chance to stake a claim for the vacant 13 shirt.
Ulster's Darren Cave will now be favourite to start at outside centre for Ireland's Tests against Argentina on 7 June in Resistencia and 14 June in Tucuman.
Ireland are yet to name a replacement for Henshaw, but losing the much-vaunted youngster will be a blow to head coach Joe Schmidt.
Former Leinster boss Schmidt will have viewed the summer tour as the ideal vehicle for blooding the next generation of centres as Ireland start the long build-up to the 2015 World Cup.
O'Driscoll retired from international rugby after his 141st Test match when Ireland edged out France in Paris to claim the RBS 6 Nations title.
The 35-year-old will bow out of professional rugby altogether in Saturday's Pro12 final when Leinster take on Glasgow in Dublin.
O'Driscoll has tipped Henshaw and Cave to lead the charge to replace him for Ireland's World Cup bid, but now Schmidt must do without his leading contender for the summer tour.