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BACKGROUND: Mozambique has a high maternal mortality ratio, and postpartum hemorrhage (PPH) is a leading cause of maternal deaths. In 2015, the Mozambican Ministry of Health (MOH) commenced a program to distribute misoprostol at the community level in selected districts as a strategy to reduce PPH. This case study uses the ExpandNet/World Health Organization (WHO) scale-up framework to examine the planning, management, and outcomes of the early expansion phase of the scale-up of misoprostol for the prevention of PPH in 2 provinces in Mozambique. METHODS: Qualitative semistructured interviews were conducted between February and October 2017 in 5 participating districts in 2 provinces. Participants included program stakeholders, health staff, community health workers (CHWs), and traditional birth attendants (TBAs). Interviews were analyzed using the ExpandNet/WHO framework alongside national policy and planning documents and notes from a 2017 national Ministry of Health maternal, newborn, and child health workshop. Outcomes were estimated using misoprostol coverage and access in 2017 for both provinces. RESULTS: The study revealed a number of barriers and facilitators to scale-up. Facilitators included a supportive political and legal environment; a clear, credible, and relevant innovation; early expansion into some Ministry of Health systems and a strong network of CHWs and TBAs. Barriers included a reduction in reach due to a shift from universal distribution to application of eligibility criteria; fear of misdirecting misoprostol for abortion or labor induction; limited communication and understanding of the national PPH prevention strategy; inadequate monitoring and evaluation; challenges with logistics systems; and the inability to engage remote TBAs. Lower coverage was found in Inhambane province than Nampula province, possibly due to NGO support and political champions. CONCLUSION: This study identified the need for a formal review of the misoprostol program to identify adaptations and to develop a systematic scale-up strategy to guide national scale-up.