From both scientific and ethical perspectives, it is important that youth be enrolled in biomedical HIV prevention clinical trials. At the same time, adolescents, as minors, are considered a vulnerable population requiring particular attention to the reduction of potential harm associated with participation in such trials. In this article, we review the evidence supporting enrollment of youth in HIV clinical trials, including data on HIV infection rates, sexual behavior, and cognitive, psychosocial, and neurophysiological development. Next, we address the potential risks associated with clinical trial participation, with a focus on the concept of preventive misconception, the tendencies to (1) overestimate the probability of assignment to the experimental condition, as opposed to the placebo, and (2) assume that the experimental intervention is efficacious. Finally, we discuss targeted interventions to reduce preventive misconception and the importance of developing and testing adolescent-friendly risk-reduction interventions that are tailored to the structure and time frame of a biomedical HIV prevention clinical trial. The very issues that make inclusion of youth in HIV prevention clinical trials necessary also demand that particularly intensive efforts be made to protect participating minors from the harm that could accrue from a clinical trial.