BACKGROUND: The 'DREAMS Partnership' promotes a multi-sectoral approach to reduce adolescent girls and young women's (AGYW) vulnerability through a core package of interventions targeting multiple sources of HIV risk-to promote Determined, Resilient, Empowered, AIDS-free, Mentored and Safe (DREAMS) lives. Implementation of such multi-sectoral programmes is complex and requires adaptation to national and local contexts. We describe the early implementation of DREAMS in diverse settings, to identify lessons for the scale-up and replication of combination programmes for young people. METHODS: As part of evaluations underway in six DREAMS sites in three countries (Kenya, South Africa and Zimbabwe), we draw on process evaluation data collected from focus group discussions, key informant interviews, and in-depth interviews with beneficiaries, parents/caregivers, programme managers and opinion leaders. Additionally, structured observations were conducted and Gantt charts completed upon consultation with implementers. We concurrently reviewed documentation available on DREAMS and held cross-site discussions to interpret findings. FINDINGS: All sites sought to implement all components of the DREAMS core package, but how and when they were implemented varied by context. Models of delivery differed, with either multiple or single partners responsible for some or all interventions. Key challenges included the urgent and ambitious expectations of DREAMS; 'layering' multiple interventions across different sectors (health, education, social welfare); supporting individuals' journeys between services to improve uptake and retention; engaging communities beyond direct beneficiaries; avoiding perceived/actual exclusivity; and ensuring continuity of commitment and funding for DREAMS. Despite significant challenges, DREAMS was well-received in the communities and perceived by both beneficiaries and implementers to empower AGYW to remain HIV negative. Structures, protocols and tools were introduced to strengthen referrals and deliver services targeted to the age and circumstances of young people. CONCLUSIONS: The benefits of combinations or integrated 'packages' of interventions are increasingly recognised. Early implementation of DREAMS provides useful lessons for improving coordination across multiple partners using a phased, systematic approach, regular adaptions to each unique context, and ensuring community ownership.