Graeme Smith will play no part in next month's ICC Champions Trophy, Cricket South Africa have confirmed.
Smith's English county Surrey revealed on Wednesday he is returning home for surgery to repair a stress fracture of the ankle.
And it could be six months before the opening batsman is back on a cricket pitch, according to South Africa team manager Mohammed Moosajee.
He said: "Graeme has been troubled by left ankle pain over the last few months and despite extensive treatment and physiotherapy, it has recently deteriorated significantly while playing for Surrey in England.
"He underwent a rescan of his left ankle and it was determined that, since his last scan, the condition has progressed to a stress fracture.
"Surgery will be required, and he has been advised to follow a rest and rehabilitation programme over the next four to six months.
"This unfortunately rules him out of the upcoming ICC Champions Trophy in England and Wales and the selectors will name a replacement in due course."
Smith's absence means AB de Villiers will captain South Africa at the Champions Trophy, which begins on June 6.
"It's a big blow for me personally to be missing out on the Champions Trophy next month. The ODI squad is creating something special and I was looking forward to being part of that family," Smith said.
"I will no doubt be supporting from my living room and I know the players, under AB's leadership will be giving all that they can during the tournament."