Research on willingness to participate in HIV vaccine trials is important in preparations for HIV vaccine research, but there are few data from sub-Saharan Africa. We interviewed 198 individuals in a peri-urban South African community immediately after enrolment into an HIV vaccine preparedness study on their willingness to participate in hypothetical vaccine trials. Overall 23% of participants (n = 46) said that they would be willing to participate in an HIV vaccine trial. Willingness was associated with increasing age, male gender, and increasing knowledge about vaccines generally and HIV vaccines specifically. In multivariate analysis, a 1-unit increase in HIV vaccine knowledge score was associated with a 10-fold increase in willingness to participate (adjusted odds ratio, 10.72, 95% confidence intervals: 4.40-26.12). These results suggest that while willingness to participate in HIV vaccine trials is relatively low in this setting, educational campaigns may have a substantial impact on individuals' willingness to participate in research.