OBJECTIVE The purpose of this study was to identify the factors that contributed to intervention effectiveness in acquired immunodeficiency syndrome (AIDS) prevention projects targeting youth. METHODS Eleven AIDS prevention projects funded by the Robert Wood Johnson Foundation whose target populations consisted of at least 60% youth were studied. A blended methodology resulted in quantitative data (i.e., survey responses) from all 11 projects supplemented with qualitative data (i.e., open-ended interviews) drawn from in-depth site visits to six projects. RESULTS Projects reported using a mean of 16.6 intervention activities (selected from a list of 30). Six activities were used by all 11 projects. Small group discussions were rated as one of three most effective activities by 72.7% of the projects that used them. Project staff identified three elements of effective interventions: involvement of peer educators, recognition of the role of adults (e.g., parents, teachers), and use of structured settings to gain access to the target population (e.g., schools, clubs). CONCLUSIONS The most powerful strategies described by project staff for reaching adolescents at risk for human immunodeficiency virus (HIV) transmission also bring considerable challenges. Opportunity costs associated with using peer educators, gatekeeper support, and structured settings may include limited control of the message, impaired credibility, and failure to reach those youth at greatest risk of HIV infection, respectively. Health educators will do well to consider the advantages and disadvantages of these factors when developing, implementing, and evaluating AIDS prevention programs for youth.