Brian O'Driscoll could miss the opener against France next Saturday with a hamstring tear; Geordan Murphy is recovering from a broken leg, and Denis Hickie has been sidelined since the World Cup with an Achilles problem.
Eric Miller has joined the trio in the treatment room with a shoulder injury, robbing Ireland - who were runners-up in last year's RBS 6 Nations - of four of their biggest names.
"I think we have some very good players in the squad and some great young players to come through. But we've been dogged by injuries - to Geordan Murphy and Denis Hickie," said O'Sullivan.
"We've also lost Eric Miller for the start of the Six Nations, and he's a world-class player.
"We have no control over injuries. But they do affect you, and it's very frustrating.
"They impact on what you can achieve, but you have to get on with it."