Background: Biomedical HIV prevention research with minors is complicated by the requirement of parental consent, which may disclose sensitive information to parents. We examine the experience of principal investigators (PIs) and study personnel who faced this complex ethical issue in the first biomedical HIV prevention study that allowed minors to self-consent for enrollment. Methods: We conducted in-depth interviews with PIs and study personnel from 13 medical trial sites in cities across the United States. Data were analyzed using a conventional content analysis. Results: Participants experienced moral conflict as they struggled to fulfill conflicting duties in this trial involving minor adolescents with multiple vulnerabilities. Our participants experienced conflict between the two types of duties—protective and scientific—previously identified by Merritt. Protective duties were owed to the child, the parents, and the institution, and participants expressed tension between the actions that would protect these subgroups and the actions necessary to fulfill their scientific duties. Conclusions: Moral conflict was resolved in a variety of ways, including reflecting on the protocol’s alignment with federal regulations, modifying consent language, considering each individual for enrollment carefully, and accepting institutional review board (IRB) decisions. Potential solutions for future studies are discussed, and include flexible protocol consent procedures and centralized IRB reviews.