Objectives: We undertook the economic evaluation of the double-blind randomized ANRS-IPERGAY trial, which showed the efficacy of on-demand preexposure prophy-laxis (PrEP) with tenofovir disoproxil fumarate (TDF)-emtricitabine (FTC) in preventing HIV infection among high-risk MSM. Design and methods: The economic evaluation was prospective. Counseling, drugs (TDF-FTC at s500.88 for 30 tablets), tests, visits, and hospital admissions were valued based on in-trial use. The cost of on-demand PrEP/HIV infection averted was compared with the yearly and lifetime costs of HIV infection in France in a cost and benefits analysis. Results: The yearly number of participants needed to treat to prevent one HIV infection was 17.6 (95% confidence interval ¼ 10.7-49.9). The annual cost of counseling was s690/participant. The total 1-year costs of PrEP were s4271/participant, of which s3129 (73%) were drug costs corresponding to 15 tablets of TDF-FTC/month. The yearly cost of on-demand PrEP to avoid one infection was s75 258. Using TDF-FTC generic (s179.9/30 tablets) reduced the 1-year costs of on-demand PrEP to s2271/ participant and s39 970/infection averted, respectively. Using TDF-FTC at international market discounted prices (s60/30 tablets) reduced the costs to s1517/participant and the cost to s26 787/infection averted, comparable with the yearly treatment cost of HIV infection in France. On-demand PrEP was found to be cost saving in France if the duration of exposure was less than 7.5 years at current drug price and 13 years at generic price. Conclusion: On-demand PrEP in high-risk MSM with TDF-FTC can be considered cost saving. Other benefits include the treatments of other diseases and reductions in secondary infections.