BACKGROUND: Development of robust treatment programs among core transmitters (CT) of hepatitis C virus (HCV) are needed, including strategies to address reinfection risk. The aim of this study was to describe the effectiveness of direct-acting antiviral (DAA) treatment in CT versus non-CT populations and assess reinfection rates after successful treatment. METHODS: Characterizing Risk Behaviour and Reinfection Rates for Successful Programs to Engage Core Transmitters in HCV Elimination (C-RESPECT) was a prospective, observational study of HCV-infected Canadian adult patients (genotypes 1, 3, and 4) treated with DAAs between 2017 and 2020. RESULTS: The full analysis set included 429 participants (259 CT, 170 non-CT). Key differences were observed in baseline profiles: CT participants were younger (mean 42.3 [SD 11.2] y versus 55.0 [SD 11.1] y, respectively) and reported higher rates of social assistance (35.7% versus 14.8%), smoking (83.7% versus 52.4%), low socioeconomic status (yearly income <$15,000: 69.6% versus 43.9%), illicit drug use (83.7% versus 34.3%), and previous incarcerations (62.7% versus 36.9%). DAA treatment adherence was similar; 93 .5% versus 98.3% of CT versus non-CT participants completed the assigned treatment duration. Cure rates (sustained virologic response) were comparable, ranging from 94.9% to 98.1%. All reinfections were among CT participants, with a rate of 13.8/100 person-years (95% CI 9.2-20.8) with mean time to reinfection of 24.6 (SD 0.6) months. CONCLUSIONS: CT and non-CT participants respond equally well to DAA treatment; however, with some reinfections among CT participants. Innovative multidisciplinary programs must be developed to mitigate this risk in this key population.