battle with brain cancer.
Professor O`Brien`s family had gathered at his bedside after his condition significantly deteriorated on Wednesday.
The acclaimed surgeon and former face of the reality TV medical program RPA, was diagnosed with an aggressive form of brain cancer in 2006.
In April, at a function to announce $100 million in federal funding for his Lifehouse at the Royal Prince Alfred Hospital cancer treatment centre, he said he had suffered a regression.
He died overnight just hours after a visit by Prime Minister Kevin Rudd.
The former head and neck cancer specialist`s obvious deterioration brought Mr Rudd to the verge of tears.
An earlier statement from Lifehouse at RPA said the surgeon was admitted to hospital on Wednesday and his family were with him.
"The O`Brien family would like to thank those who have supported Chris and his work with the Sydney Cancer Centre over the past few years," Lifehouse said.
"They request that his privacy now be respected during this very difficult time."
Building works on the project which will become Prof O`Brien`s legacy begins in Camperdown at the end of 2009.
When completed in 2012 it will be Australia`s largest cancer care centre.
Mr Rudd paid tribute to Prof O`Brien at April`s function in Sydney, saying he considered the former surgeon a "friend" and "inspiration".
"In the two years since I`ve known Chris, I`ve come to respect him deeply, to admire him deeply, to love him deeply as a first class human being," Mr Rudd said.
"It is one of the terrible ironies of life that a man like Chris would be diagnosed with the very type of cancer he did so much to fight against with his own patients."