This study examined the net effects of refining a high school-based indicated drug prevention program. The Personal Growth Class (PGC), tailored to meet the needs of high-risk youth, was designed to increase control of drug use, school performance, and emotional well-being. The program integrates social support and life-skills training. Process evaluation revealed the need for program enhancements to address underestimated levels of depression, anger, and suicidal behaviors prevalent among high-risk youth and to ensure that core content was being emphasized consistently. Youth participating in Late cohorts received the refined PGC with enhanced skills training. Study participants (N = 280) were youth, primarily ages fifteen to-seventeen, at high-risk for school failure or dropout. Indicators of emotional well-being (e.g., depression, stress, anger, self-esteem, personal control), drug involvement, and school performance were compared for Late versus Early cohorts. Regression analyses revealed the Late versus Early cohorts showed significantly greater decreases in hard drug use, depression, perceived stress, and anger, and greater increases in self-esteem. The results support arguments that effective indicated prevention programs should target specific high-risk youth employing strategies to counteract the multifaceted risk factors they experience and enhance needed protective factors.