The disease "carries the face of women," whether through infection or caring for those who are ill with the deadly virus, said the 86-year-old Mandela.
Mandela, who lost his eldest son to the disease earlier this year, compared the plight of women coping with AIDS to the isolation he felt when imprisoned for 27 years on Robben Island for fighting against white racist rule.
"Today there are millions of women in Africa living on their own Robben Islands, struggling against terrible odds, alone and often without much hope," he said.
"Tonight you and I can say we are here to help give you hope and strength," he said to rapturous applause at the 46664 concert, named for his prisoner number. He sponsored a first AIDS conference in 1993 in Cape Town. The Saturday benefit, he said, raised $1.6 million.
Gertrude Maqanda, a woman from a poor township near the popular tourist coastal resort of George, told how she nearly died last year until she received antiretroviral treatment. She contracted the virus in 1999.
"I love you very much," she said, prompting a temporary hush in the crowd and an embrace from master of ceremonies, superstar Will Smith.
The American actor and singer said he agreed to a personal request from Mandela to be an ambassador for the 46664 campaign.
"I have made movies and music," said the star of "Men in Black" and "Independence Day."
"I felt like that's not enough. I want to fight and I want to struggle," he said.
In South Africa, statistics show women and girls are six times more likely to be infected with the AIDS virus than men. A staggering 38 percent of pregnant women are infected in the worst hit province of Kwazulu-Natal.
Overall, an estimated 5.3 million of South Africa's 45 million people live with HIV, more than in any other country. Between 600 and 1,000 are dying every day from AIDS related diseases, according to U.N. figures.
"In Africa more people are wiped out by AIDS ever year than in the entire Asian Tsunami disaster," said former Eurythmics star Annie Lennox. "In this society women are powerless and vulnerable to the whims of men who refuse to practice safe sex and use condoms."
Star after star appealed to men to take responsibility and stop unsafe sex — and to women to stand up for their rights.
"I want you to use your power to stay alive," shouted Jada Pinkett Smith, Will Smith's wife.
Since stepping down as South Africa's first black president in 1999, Mandela has championed the cause of AIDS victims.
"You may well ask, what is this old age pensioner doing here tonight, when he is supposed to have retired?" he asked.
"Yes, I would love to enjoy the peace and quiet of retirement, but I know that like many of you, I cannot rest easily while our beloved continent is ravaged by a deadly epidemic."