On-demand pre-exposure prophylaxis (PrEP) taken before and after sex—known as PrEP 2-1-1—is as effective and well tolerated as daily pills, according to the French PREVENIR study. PrEP 2-1-1 involves taking two doses of tenofovir disoproxil fumarate/emtricitabine (TDF/FTC, sold as Truvada or generic equivalents) two to 24 hours before anticipated sex, one dose 24 hours later and a final dose 24 hours after that. PREVENIR enrolled more than 3,000 HIV-negative adults, mostly gay and bisexual men. They could opt to take TDF/FTC either as one pill each day or using the PrEP 2-1-1 schedule; about half chose each option. There were three HIV seroconversions in the daily PrEP group and three in the on-demand group. Although not yet approved by the Food and Drug Administration, PrEP guidance from the Centers for Disease Control and Prevention includes information about off-label prescribing of PrEP 2-1-1, and some cities offer it as an option. More research is needed to assess whether on-demand PrEP works for other populations, including women.