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Although the role of mobile populations in the spread of HIV has been documented in several countries, there are few data on HIV among truck drivers in South Africa and the sex workers with whom they interact.To determine HIV prevalence and risk behavior in a sample of truck drivers visiting commercial sex workers at truck stops.Two sex workers from each of five truck stops were trained to obtain informed consent, administer questionnaires to obtain data on demographic and migration patterns, and collect saliva samples for HIV testing from their clients. Data on HIV prevalence and demographic characteristics of sex workers operating at the truck stops were obtained from an ongoing vaginal microbicide trial.The mean age of the truck drivers (all men) was 37 years (range, 18–71 years), and that of the sex workers (all females) was 25 years (range, 15–49 years). Sixty-six percent of the men reported having a sexually transmitted infection in the previous six months, and 37% always stopped for sex along the route. Twenty-nine percent reported never using condoms with sex workers, whereas 13% had used condoms with their wives. All men traveled to more than one province in South Africa, and 65% traveled to neighboring countries. Anal sex was practiced by 42% of the men. The overall HIV prevalence (in the two groups combined) was 56%.Truck drivers may have facilitated the spread of HIV infection throughout southern Africa.