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The objective of this study was to estimate the cost-effectiveness of syndromic management, with and without periodic presumptive treatment (PPT), in averting sexually transmitted infections (STIs) and HIV in female sex workers (FSWs) participating in a hotel-based intervention in Johannesburg.Financial and economic providers' costs were estimated. A mathematical model, fitted to epidemiologic data, projected the HIV and STIs averted by the intervention. Cost per HIV infection and DALY averted were estimated for different general population HIV prevalences.Projections suggest 53 HIV infections were averted (July 2000–June 2001) and a 3.1% decrease in the FSW HIV incidence. Cost-effectiveness was $78 per DALY averted. Incremental cost of PPT was $31 per disability-adjusted life year (DALY) averted. Initiating the intervention at 15% general HIV prevalence would have improved cost-effectiveness by 35%. Expanding PPT coverage to mass-treat all FSWs (instead of <17%) and their clients could increase impact 14-fold.The results highlight targeted interventions can be cost-effective at all stages of HIV epidemics and suggests PPT could improve the cost-effectiveness of targeted STI interventions.