When he was released from prison in February 1990, HIV/Aids had yet to make its full impact on South Africa.
But when his own son Makgatho died from Aids-related illness in 2005, Mandela tackled the taboo head-on and break Africa's silence of the past in regard to the epidemic.
"Nelson Mandela was a central figure in the Aids movement. He was instrumental in laying the foundations of the modern Aids response," said Michel Sidibe, head of the Joint UN Programme on HIV/Aids, Unaids.
"His actions helped save millions of lives and transformed health in Africa. He broke the conspiracy of silence and gave hope that all people should live with dignity."
According to UN figures, the rate of HIV infection among adult South Africans rose from less than 1% in 1990 to about 17.9% by 2012.
South Africa is currently home to more people with the virus than any other country - 6.1 million of its citizens were HIV positive in 2012, including 410,000 children, out of a population of just in excess of 51 million.
Poverty, economic migration, the poor status of women and unsafe sexual practices have all contributed to the rapid spread of the disease.
The Global Fund to Fight Aids, Tuberculosis and Malaria paid tribute to Mandela's "special role" as a breaker of taboo.
"While other political leaders denied or ignored the spread of HIV, causing severe damage by hindering the implementation of effective treatment, Mandela spoke openly," it said.
The International Aids Society (IAS) said the world "has lost an extraordinary statesman and human being".
"Mr Mandela had the power to change hearts and minds, change policies and above all change the public's perception of the virus in the most affected region of sub-Sahara," said Bertrand Audoin, executive director of the IAS.
Failure to address the Aids crisis in his country has been singled out as a weak spot in Mandela's record as the first president of post-apartheid South Africa, from 1994-1999.
But activists say that after he left office, stung by awareness of the problem, he threw himself into combating discrimination and ramping up access to life-saving drugs through his 46664 Foundation, say activists.