OBJECTIVE: Estimate the potential impact of Avahan, the India AIDS Initiative, among female sex workers (FSWs) and their clients in five districts of Karnataka state, south India. DESIGN: Examination of time trends in sexually transmitted infection (STI)/HIV prevalence from serial cross-sectional surveys, combined with mathematical modelling. METHODS: Survey data from each district were used to monitor changes in FSW STI/HIV prevalence during Avahan. A deterministic model, parameterized with district-specific survey data, was used to simulate HIV/HSV-2/syphilis transmission among high-risk groups in each district. Latin hypercube sampling was used to obtain multiple parameter sets that reproduced district-specific HIV prevalence trends. A Bayesian framework tested whether self-reported increases in consistent condom use (CCU) during Avahan were more compatible with FSW HIV prevalence trends than assuming no or slow (preintervention rates) CCU increases, and were used to estimate HIV incidence and infections averted. RESULTS: Declines in FSW HIV prevalence occurred over 5 years in all districts, and were statistically significant in three. Self-reported increases in CCU were more consistent with observed declines in HIV prevalence in three districts. In all five districts, an estimated 25-64% (32-70%) HIV infections were averted among FSWs (clients) over 5 years. This corresponded to 142-2092 FSW infections averted depending on the district (two-fold to nine-fold more among clients). CONCLUSION: Empirical HIV prevalence trends combined with Bayesian modelling have provided plausible evidence that Avahan has reduced HIV transmission among FSWs and their clients. If current CCU levels are sustained, FSW HIV prevalence could decline to low levels by 2015, with many more infections averted.