Adolescent sexual and reproductive health gained particular traction in Mozambique following the 1994 International Conference on Population and Development leading to the inception of Programa Geração Biz (PGB), a multi-sectoral initiative that was piloted starting in 1999 and fully scaled-up to all provinces by 2007. We conducted a systematic review of the literature to gather information on PGB and analyzed how it planned and managed the scale-up effort using the WHO-ExpandNet framework. PGB's activities comprised a clear and credible innovation. Appropriate resource and user organizations further facilitated national scale-up. Challenges relating to the complex nature of the multi-sectoral approach and resistance due to norms about adolescent sexual and reproductive health hindered scaling-up in some geographic areas. The national government exhibited commitment and ownership to PGB through budgetary support and integration into multiple policies. This study adds to the documentation of successful scaling-up strategies that can provide guidance for policy makers and programme managers.