Developing and disseminating a preventive HIV vaccine is a primary scientific and public health objective. However, little is known about HIV vaccine acceptability in the high-prevalence setting of South Africa- where young adults are likely to be targeted in early dissemination efforts. This study reports on six focus groups (n = 42) conducted in 2007 with South Africans aged 18 to 24 years. A deductive framework approach is used to identify key motivators and barriers to future HIV vaccine uptake. Participants identify HIV testing, HIV stigma, mistrust of the health care system, and concerns about sexual disinhibition as barriers to vaccine uptake. For women, family members and friends are strong motivators for vaccine uptake, whereas men are more likely to see vaccines as an opportunity to stop using HIV prevention strategies such as condoms and partner reduction. Implications of these findings for developing HIV vaccine dissemination strategies and policy in South Africa are discussed.