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To assess the cost-effectiveness of HIV post-exposure prophylaxis (PEP) in France.We used a decision tree to evaluate, from a society's perspective, the cost of PEP per quality-adjusted life-year (QALY) saved. We used 1999–2003 PEP surveillance data and literature-derived data on per event transmission probabilities, PEP efficacy and quality of life with HIV. HIV prevalence and lifetime cost of HIV/AIDS management in the HAART era were derived from French studies. We assumed that mean life expectancy in full health was 65 years among uninfected individuals and that the mean survival time after HIV infection was 22.5 years. The costs of PEP drugs and follow-up were derived from the French public sector. A 3% annual rate was used to discount future costs and effects.During 1999–2003, PEP was prescribed to 8958 individuals (heterosexual sex: 47.6%; homosexual sex: 28.4%; occupational exposure: 23.4%; drug injection: 0.6%); of those, 2143 were exposed to a known HIV-infected source. PEP was estimated to prevent 7.7 infections and saved 64.5 QALY at a net cost of €5.7 million, resulting in an overall cost-effectiveness ratio of €88 692 per QALY saved. PEP was cost saving for 4.4% of cases and cost effective (< €50 000 per QALY) in a further 11.3% of cases. In contrast, 72 and 52% of prescriptions had a cost-effectiveness ratio exceeding €200 000 and €2 millions, respectively, per QALY saved.Overall, the French PEP programme is only moderately cost effective. PEP guidelines should be revised to target high-risk exposures better.