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Abstract Background and Aims Hepatitis C (HCV) programs face challenges, especially linked to key populations to achieve World Health Organization (WHO) goals of eliminating hepatitis. Médecins Sans Frontières and Mozambique's Ministry of Health first implemented HCV treatment in Maputo, in 2016 and harm reduction activities in 2017. Methods We retrospectively analyzed routine data of patients enrolled between December 2016 and July 2021. Genotyping was systematically requested up to 2018 and subsequently in cases of treatment failure. Sustainable virological response was assessed 12 weeks after the end of treatment by sofosbuvir‐daclatasvir or sofosbuvir‐velpatasvir. Results Two hundred and two patients were enrolled, with 159 (78.71%) males (median age: 41 years [interquartile range (IQR): 37.10, 47.00]). Risk factors included drug use (142/202; 70.29%). One hundred and eleven genotyping results indicated genotype 1 predominant (87/111; 78.37%). Sixteen patients presented genotype 4, with various subtypes. The people who used drugs and HIV coinfected patients were found more likely to present a genotype 1. Intention‐to‐treat analysis showed 68.99% (89/129) cure rate among the patients initiated and per‐protocol analysis, 88.12% (89/101) cure rate. Nineteen patients received treatment integrated with opioid substitution therapy, with a 100% cure rate versus 59.37% (38/64) for initiated ones without substitution therapy (p