Introduction Data on the epidemiology of hepatitis C among individuals who use drugs in low-threshold settings are lacking, although crucial to assess the burden of disease and aid in the design of treatment strategies. Objective The aim of this study was to characterize the epidemiology and disease related to hepatitis C in a population attending a low-threshold methadone program. Materials and methods A cross-sectional study in the population attending the Mobile Low-Threshold Methadone Program in Lisbon, Portugal, was carried out. The survey included assessment of risk factors for infection with hepatitis C virus (HCV) and liver disease, HCV serology and RNA detection, HCV genotyping, and liver disease staging. Results A total of 825 participants were enrolled, 81.3% men, mean age 44.5 years. Injecting drug use (IDU) was reported by 58.4% - among these, 28.2% were people who inject drugs. Excessive drinking and HIV coinfection were reported by 33.4 and 15.9%, respectively. Among participants with active infection, 16.9% were followed up in hospital consultation. The overall seroprevalence for HCV was 67.6% (94.2% in IDU, 30.0% in non-IDU, 97.1% in people who inject drugs, and 75.6% in excessive drinkers). Among seropositives for HCV, active infection was present in 68.4%. Among individuals with active infection, the most common genotypes were 1a (45.3%) and 3a (28.7%), whereas 30% had severe liver fibrosis or cirrhosis. Age 45 years or older, HCV genotype 3, and coinfection with HIV were significant predictors of cirrhosis. Conclusion This population has a high burden of hepatitis C and several characteristics that favor dissemination of infection. Healthcare strategies are urgently needed to address hepatitis C in this setting. Copyright (C) 2017 Wolters Kluwer Health, Inc. All rights reserved.