Sexual transmission represents the principal mode of transmission for human immunodeficiency virus type 1 (HIV-1) worldwide. We examined the HIV-1 seroprevalence and risk factors for infection among 613 female commercial sex workers (FCSW) in Isla Margarita, Venezuela. Recruitment was conducted in street venues and working locations. None of the FCSW tested positive for HIV; this correlated with the low self-reported rates of sexually transmitted infections (6%), drug use (<20%), and alcohol abuse (12%). Condom use and safe-sex practices were found to be practiced regularly (>80% of time) with clients; however, such practices were found to be very uncommon in nonclient relations (<20% of the time). Understanding the sexual risk behaviors, beliefs, and drug use patterns of FCSW is important for future development of effective public prevention policies and educational campaigns aimed at decreasing the risk of infection with HIV-1 and other sexually transmitted infections among FCSW.