To systematically review the evidence for effectiveness of HIV and sexually transmitted infection (STI) prevention interventions in female sex workers in resource poor settings. Published and unpublished studies were identified through electronic databases (Cochrane database, Medline, Embase, and Web of Science), hand searching and contacting experts. Randomized-controlled-trials and quasi-experimental studies were included if they were conducted in female sex workers from low and middle income settings; if the exposure was described; if the outcome was externally measurable, it was after the discovery of HIV, and if follow-up was longer than 6 months. A priori criteria were used to extract data. Meta-analysis was not performed due to the heterogeneity of studies. Twenty-eight interventions were included. Despite methodological limitations, the evidence suggested that combining sexual risk reduction, condom promotion and improved access to STI treatment reduces HIV and STI acquisition in sex workers receiving the intervention. Strong evidence that regular STI screening or periodic treatment of STIs confers additional protection against HIV was lacking. It appears that structural interventions, policy change or empowerment of sex workers, reduce the prevalence of STIs and HIV. Rigorous evaluation of HIV/STI prevention interventions in sex workers is challenging. There is some evidence for the efficacy of multi-component interventions, and/or structural interventions. The effect of these interventions on the wider population has rarely been evaluated.