Tshabalala-Msimang underwent a five-hour liver transplant at the Donald Gordon Medical Centre on March 14 2007 and in November was readmitted to hospital with complications.
Never far from controversy, Tshabalala-Msimang's views on the treatment of HIV/Aids drew international condemnation, especially her advocacy of beetroot, garlic, and African potatoes as nutritional supplements to fight the disease.
This led to her being dubbed "Dr Beetroot" by critics.
Her views on the use of antiretroviral (ARV) drugs in the treatment of Aids often provoked vehement opposition from both Aids activists and experts alike.
In 2004, she said: "I have always said there are three options... and we must remember that ARVs are not a cure and they do have side-effects."
She said at the time that garlic, lemon, olive oil and beetroot "are absolutely critical - first of all to have a beautiful face and beautiful skin - but they also protect you from disease".
Tshabalala-Msimang was widely seen as championing former president Thabo Mbeki's views on Aids, and was supportive of so-called Aids dissidents, who questioned the link between HIV and Aids, and pinned the cause of the disease on nutritional deficiencies.
Calls were made to Mbeki to remove his health minister, but these were not heeded by the president.
Another controversial issue during Tshabalala-Msimang's tenure as health minister were her efforts to reduce the cost of medicines to the public.
These raised the ire of pharmacists around South Africa, who took her to court, claiming she was threatening their continued existence.
She also created a media ethics debate over the reporting of information deemed to be between a doctor and a patient when she was in hospital.
The Sunday Times had reported that in spite of her condition she was consuming alcohol, and had sent hospital staff to purchase wine.
The reaction to her death has also been controversial. "Manto is dead. Good. A selfish and wicked bungler of the lowest order," tweeted DJ Gareth Cliff after the news broke. Followers of the popular DJ on Twitter, including blogger Khaya Dlanga, disagreed.
"I have lost members of my own family to AIDS, if anyone should be rejoicing it's me. Do you see me doing so, Gareth Cliff" replied Dlanga.
"Twitter is an indication of the cultural divide everpresent in South Africa... Dr Manto Tshabalala-Msimang, was a mother, a daughter, a human being. The respect you pay her in death is respect to those she left behind," tweeted @iamsuede.
What do you think of the reaction to Manto Tshabalala-Msimang's death? How will she be remembered by the South African public and do you think this is fair? Let us know in the comments box below.