BACKGROUND: Daily oral pre-exposure prophylaxis (PrEP) can reduce HIV infection in adolescent girls and young women if used consistently during periods of risk. The EMPOWER study evaluated peer-based clubs incorporating an empowerment curriculum offered to adolescent girls and young women (16-24 years) in South Africa and Tanzania for adherence support. METHODS: Using serial in-depth interviews (n = 33), we assessed the benefits and challenges of club attendance among 13 EMPOWER participants in the Johannesburg site who were randomised to clubs. We used a summary matrix of coded data to support a narrative, case-based analysis. Four case studies are presented. RESULTS: Club participants reported benefits such as increased self-esteem and self-efficacy, reduced isolation, and greater insight into gender-based violence and strategies to address it. Day-to-day PrEP adherence was not the only topic discussed in clubs; participants also appreciated the safe space for sharing problems (such as relationship conflict and PrEP stigma) and found interactive exercises helpful in improving partner communication. CONCLUSIONS: Findings support the use of peer-based clubs using a structured empowerment approach, which may offer valuable PrEP initiation support to adolescent girls and young women in settings with high HIV and gender-based violence prevalence. TRIAL REGISTRATION: Pan African Clinical Trials Registry PACTR202006754762723 , 5 April  2020, retrospectively registered.