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Introduction: Virtually no African country provides HIV prevention services in sex work settings with an adequate scale and intensity. Uncertainty remains about the optimal set of interventions and mode of delivery. Methods: We systematically reviewed studies reporting interventions for reducing HIV transmission among female sex workers in sub-Saharan Africa between January 2000 and July 2011. Medline (PubMed) and non-indexed journals were searched for studies with quantitative study outcomes. Results: We located 26 studies, including seven randomized trials. Evidence supports implementation of the following interventions to reduce unprotected sex among female sex workers: peer-mediated condom promotion, risk-reduction counselling and skills-building for safer sex. One study found that interventions to counter hazardous alcohol-use lowered unprotected sex. Data also show effectiveness of screening for sexually transmitted infections (STIs) and syndromic STI treatment, but experience with periodic presumptive treatment is limited. HIV testing and counselling is essential for facilitating sex workers' access to care and antiretroviral treatment (ART), but testing models for sex workers and indeed for ART access are little studied, as are structural interventions, which create conditions conducive for risk reduction. With the exception of Senegal, persistent criminalization of sex work across Africa reduces sex workers' control over working conditions and impedes their access to health services. It also obstructs health-service provision and legal protection. Conclusions: There is sufficient evidence of effectiveness of targeted interventions with female sex workers in Africa to inform delivery of services for this population. With improved planning and political will, services - including peer interventions, condom promotion and STI screening - would act at multiple levels to reduce HIV exposure and transmission efficiency among sex workers. Initiatives are required to enhance access to HIV testing and ART for sex workers, using current CD4 thresholds, or possibly earlier for prevention. Services implemented at sufficient scale and intensity also serve as a platform for subsequent community mobilization and sex worker empowerment, and alleviate a major source of incident infection sustaining even generalized HIV epidemics. Ultimately, structural and legal changes that align public health and human rights are needed to ensure that sex workers on the continent are adequately protected from HIV.