The trial of a new vaginal gel among 889 women in KwaZulu-Natal found that 38 women using it got HIV, compared to 60 who got HIV and were not using the gel.
And 54% fewer got the virus when applying the gel as instructed - using an applicator to insert the gel within 12 hours of sex, and again afterwards.
At the International Aids Conference in Vienna, lead researchers Salim and Quarraisha Abdool Karim were hailed as pioneers of "a new hope for women".
The couple, who celebrate their 50th birthdays this week, explained how chance meetings, hustles, tragic setbacks and pioneering science led to the breakthrough.
The story started 25 years ago when Durban doctor Salim persuaded his university girlfriend to follow him to the US to join an Aids study programme. Here, their mentor, South African-born Aids activist Zena Stein, warned the couple that, without a tool to protect themselves, women would one day become the primary victims of HIV - and, indeed, women now make up 60% of all new infections.
However, the maiden test of a vaginal gel, in 1994, failed to show a benefit for the women in the trial.
In 1999 the couple were shocked to learn that of the sex workers in their latest trial, 48% more had been infected with HIV than the women who weren't using the gel. "We had actually been causing harm," said Salim.
The aim was to try to block the virus from entering a woman's body.
But after the failure of a total of 11 different trials, the Karims turned to antiretroviral drug Nevirapine, which prevents the infection being passed on to babies of HIV-positive mothers if it is administered within 12 hours of birth.
The couple liked the idea of a gel that women could use within 12 hours of sex - time enough that their male partners need not even be aware of it - and Salim believed an antiretroviral would work in a gel. It wouldn't block the virus, but it would prevent it from growing inside a woman's cells instead.
Meanwhile, Salim was "blown away" by a US medical paper which showed that monkeys injected with another ARV, called Tenofovir, were protected against simian HIV.
Quarraisha said the turning point came at an Aids conference in Thailand in July 2004, when protesters destroyed a stand erected by US drug company Gilead, which made Tenofovir tablets.
While he commiserated with Gilead's head of research over the protest, Salim learned about the drug's lack of serious side effects.
On October 14 2004, Salim flew to Gilead's headquarters in California, and managed to persuade the company to donate 30kg of their drug in powder form. He also got them to give up any royalties for a future gel, to lend him their experts - and even to sign over the licence to South Africa for distribution in Africa.
Quarraisha said: "Salim could sell ice to Eskimos."
Through some incredible good luck - like sitting next to a key official from funding agency USAID at lunch - the couple managed to get money and find someone who could make the gel.
Finding agreement on a 1% solution of the drug for a gel, the scientist then bought 250000 applicators and got yet another US company to agree to fill them with the solution.
Then the trial hit a new crisis of criticism: a damning article in scientific journal Nature, and an anonymous complaint to USAID.
Salim's second mentor, Professor Hoosen Coovadia, said: "There was robust opposition - concerns that use of the drug in a gel could create resistance ... But he won the debate. As a collaboration, Salim and Quarraisha are a formidable force in this field."
Although he confirmed that the notorious Aids denialist and minister of health, Manto Tshabala-Msimang, had sought to derail the trial, Salim said he preferred not to discuss the details.
On May 28 this year, the Karims and four other investigators were finally shown the infection figures for those who had used the gel - "and there was this stunned silence".
The Karims will now try to improve the gel. Salim said he hoped a cheap and more effective version of the gel would be available in about three years.
Mommacyndi