Both of Ireland's centres, O'Driscoll and 2004 Player of the tournament Gordon D'Arcy were forced off in either half at the Stadio Flaminio with hamstring injuries.
''Brian and Gordon have damaged hamstrings. It's probably the worst possible scenario for us at the moment," said coach Eddie O'Sullivan afterwards.
He conceded D'Arcy was "very doubtful" for next Saturday's Murrayfield clash with Scotland, while RBS man-of-the-match O'Driscoll - who set up tries for Geordan Murphy and Peter Stringer, and watched Leinster team mate Denis Hickie draw within one of his try record of 25 late on - is also a worry.
A concerted early effort from John Kirwan's home outfit - searching for their fourth tournament scalp in six seasons - saw Ireland pegged back in their own half for much of the opening 20 minutes.
Argentine-born fly-half Luciano Orquera missed his opening shot, but clipped over a closer seventh-minute attempt for a 3-0 Italy lead.
With his opposite number Ronan O'Gara struggling to secure field position for the visitors with the heavier Mitre G-Spin ball, possession and territory were the Italians' - unfortunately, in the absence of retired record points scorer Diego Dominguez, the points were not.
O'Gara was allowed to level things up on 22 minutes, after 23-year-old Orquera had coughed up two more place kick chances.
With the Italian back row trio of Aaron Persico, Mauro Bergamasco and the returning Sergio Parisse revelling in the early nerve-jangling stages, O'Driscoll calmed the visitors' nerves with an effortless break for Murphy's try.
The skipper sped past Gonzalo Canale over halfway on a dummy scissors move with Denis Leamy, and took a heavy hit from Roland De Marigny before sending full-back Murphy skittling over in the left corner, under the challenge of Ludovico Nitoglia.
O'Gara missed the conversion - twice, due to Nitoglia's over-zealousness - and although Orquera fluffed two more shots - one a 30-metre drop goal - De Marigny assumed the kicking duties and drilled over superbly from 46 metres, to leave Kirwan's charges two behind at the break - 8-6.
Parma back De Marigny clawed Italy back in front, four minutes after the restart but as Ireland began to assert more control, the tries duly came.
Starved of any clean ball, it took O'Driscoll again to tear through the Italian midfield, this time giving Murphy the chance to take it on, and with the ball eventually finding its way to Shane Horgan wide on the left, his well-timed overhead pass - with a foot almost in touch - found scrum-half Stringer who ghosted clean through from five metres out.
O'Gara's acute conversion - his best kick of the afternoon - pushed the Irish 15-9 in front with just over half-an-hour remaining. He traded further penalties with De Marigny, but Italy still held more in reserve.
Nitoglia - making his first Six Nations start - knocked on over the Irish line on 66 minutes, in the process of scoring, and O'Driscoll was forced to repel Andrea Masi as Italy saw their barracking maul make fitful gains.
Munster lock Paul O'Connell was at the forefront of the Irish defence, and he took the top tackle count honours with seven, one ahead of the tireless O'Driscoll.
O'Gara's third penalty buffered the Irish lead and quick hands from Stringer and Murphy again, helped Hickie dart over for a converted 76th-minute score.
Having not scored a try in their two previous meetings with the men-in-green, Italy went down the other end, building up another head of steam in the forwards, for prop Martin Castrogiovanni to deservedly burrow over in injury time.
A valiant effort by Italy, saluting the ever decreasing gap between the supposed two tiers in the tournament. A gutsy win for O'Sullivan's men however - one which was not pretty, but it did not need to be.
Two points are two points, Ireland sit top of the pile and Murrayfield and Matt Williams await.
RBS SIX NATIONS CHAMPIONSHIP:Italy 17 Ireland 28, Stadio Flaminio, RomeScorers: Try: Martin Castrogiovanni; Pens: Luciano Oruqera, Roland de MarignyIreland: Tries: Geordan Murphy, Peter Stringer, Denis Hickie; Cons: Ronan O'Gara 2; Pens: O'Gara 3
(15) Roland De Marigny(14) Mirco Bergamasco(13) Gonzalo Canale(12) Andrea Masi(11) Ludovico Nitoglia
Replacements used: Carlo Antonio Del Fava for Dellape (66 mins), Paul Kaine Robertson for Canale (71), Giorgio Intoppa for Lo Cicero, Salvatore Perugini for Ongaro, David Dal Maso for Parisse (all 80). Not used: Paul Griffen, Walter Pozzebon.
(15) Geordan Murphy(14) Shane Horgan(13) Brian O'Driscoll (Capt)(12) Gordon D'Arcy(11) Denis Hickie(10) Ronan O''Gara(9) Peter Stringer(1) Reggie Corrigan(2) Shane Byrne(3) John Hayes(4) Malcolm O'Kelly(5) Paul O'Connell(6) Simon Easterby(7) Denis Leamy(8) Anthony Foley
Replacements used: Girvan Dempsey for D'Arcy (29 mins), Marcus Horan for Corrigan (61), Frankie Sheahan for Byrne, Donncha O'Callaghan for O'Connell, Eric Miller for Foley (all 77). Not used: Guy Easterby, David Humphreys.
HT: Italy 6 Ireland 8; Attendance: 25,000Referee: Paddy O'Brien (New Zealand)