Sex work occurs in many forms and sex workers of all genders have been affected by HIV epidemics worldwide. The determinants of HIV risk associated with sex work occur at several levels, including individual biological and behavioural, dyadic and network, and community and social environmental levels. Evidence indicates that effective HIV prevention packages for sex workers should include combinations of biomedical, behavioural, and structural interventions tailored to local contexts, and be led and implemented by sex worker communities. A model simulation based on the South African heterosexual epidemic suggests that condom promotion and distribution programmes in South Africa have already reduced HIV incidence in sex workers and their clients by more than 70 . Under optimistic model assumptions, oral pre-exposure prophylaxis together with test and treat programmes could further reduce HIV incidence in South African sex workers and their clients by up to 40 over a 10-year period. Combining these biomedical approaches with a prevention package, including behavioural and structural components as part of a community-driven approach, will help to reduce HIV infection in sex workers in different settings worldwide.