BACKGROUND: HIV/AIDS remains a leading cause of death in adolescents (aged 15 - 25 years), and in sub-Saharan Africa HIV-related deaths continue to rise in this age group despite a decline in both adult and paediatric populations. This is attributable in part to high adolescent infection rates and supports the urgent need for more efficacious prevention strategies. In particular, an even partially effective HIV vaccine, given prior to sexual debut, is predicted to significantly curb adolescent infection rates. While adolescents have indicated willingness to participate in HIV vaccine trials, there are concerns around safety, uptake, adherence, and ethical and logistic issues. OBJECTIVES: To initiate a national, multisite project with the aim of identifying obstacles to conducting adolescent HIV vaccine trials in South Africa (SA). METHOD: A simulated HIV vaccine trial was conducted in adolescents aged 12 - 17 years across five SA research sites, using the already licensed Merck human papillomavirus vaccine Gardasil as a proxy for an HIV vaccine. Adolescents were recruited at community venues and, following a vaccine discussion group, invited to participate in the trial. Consent for trial enrolment was obtained from a parent or legal guardian, and participants aged 16 - 17 years were eligible only if sexually active. Typical vaccine trial procedures were applied during the five study visits, including the administration of vaccination injections at study visits 2, 3 and 4. RESULTS: The median age of participants was 14 years (interquartile range 13 - 15), with 81% between the ages of 12 and 15 years at enrolment. Overall, 98% of screened participants opted to receive the vaccine, 588 participants enrolled, and 524 (89%) attended the final visit. CONCLUSIONS: This trial showed that adolescents can be recruited, enrolled and retained in clinical prevention trials with parental support. While promising, these results were tempered by the coupling of sexual-risk eligibility criteria and the requirement for parental/guardian consent, which was probably a barrier to the enrolment of high-risk older adolescents. Further debate around appropriate consent approaches for such adolescents in HIV prevention studies is required.