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Development of a global HIV vaccine will require enrollment of a large number of adults and adolescents in clinical trials. Involvement of homeless young adults in these trials will be particularly important because they often practice high-risk behaviors and are disproportionately infected by HIV. This qualitative study explores factors that might affect future participation of homeless 18- to 24-year-olds of diverse racial/ethnic backgrounds in HIV vaccine trials (HIVVTs). Twenty males and females attended focus groups. Participants expressed concern about seroconversion, the trustworthiness of the researchers and/or government agencies conducting trials, vaccine side effects, and possible negative behavior change as a result of being vaccinated. Understanding the personal perspectives of high-risk young adults will enable researchers to tailor protocols to their individual needs and cultural values and, in so doing, potentially enhance willingness to participate in HIVVTs.