Gay men can now take three pills - one before sex and two over the next two days - to protect themselves against HIV.
The Ipergay trial in France found that gay men who complied with the treatment regimen reduced their likelihood of contracting HIV by 86%.
The results of the trial were announced on Monday in Seattle, in the US, at the Conference on Retroviruses and Opportunistic Infections.
The pills could be a game-changer in the fight against the spread of HIV/Aids among gay men.
They do not have to be taken every day but only when the man is sexually active.
It has been found that most healthy people are not sufficiently motivated to take a tablet every day to prevent HIV.
The drug under trial, Truvada, is a combination of two antiretrovirals: tenofovir and emtricitabine.
It is licensed by the Food and Drug Administration in the US for daily use by gay men as a method of HIV prevention.
Researchers initiated the study to determine if Truvada could be used solely as an "on demand" medication.
Four hundred promiscuous gay men who had sex without a condom were recruited for the Ipergay study.
Half of them were given the drug; the other half a placebo.
The treatment was so successful that the Ipergay monitoring board stopped the study early. It would have been unethical to continue giving one group of men a placebo.
In the group of men who received the real pill, there were only two HIV infections.
But there were 14 in the group given the placebo.
The researchers had told the study participants to practise safe sex at all times and not rely on the trial medication.
Professor James McIntyre, of South African NGO Anova, which runs gay-friendly clinics, said the study results "herald an exciting and bold new era in HIV prevention for men who have sex with men - a population at particular risk of both acquiring and transmitting the virus".
Last year McIntyre's organisation received money from the Elton John Foundation to provide Truvada to gay men who use Anova's South African clinics.
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