Little is known about how a sustained virologic response (SVR) to treatment of hepatitis C virus (HCV) infection with direct-acting antivirals (DAAs) affects patient mortality and development of new liver-related events. We aimed to evaluate the incidence of disease progression in patients treated with DAAs.We performed a prospective multicenter cohort study of 1760 patients who received DAA treatment at 23 hospitals in Latin America, from May 1, 2016 through November 21, 2019. We excluded patients with history of liver decompensation, hepatocellular carcinoma (HCC), or solid organ transplantation. Disease progression following initiation of DAA therapy included any of the following new events: liver decompensation, HCC, liver transplantation, or death. Evaluation of variables associated with the primary outcome was conducted using time-dependent Cox proportional hazards models.During a median follow-up of 26.2 months (interquartile range, 15.3-37.5), the overall cumulative incidence of disease progression was 4.1% (95% CI, 3.2%-5.1%) and following SVR assessment was 3.6% (95% CI, 2.7%-4.7%). Baseline variables associated with disease progression were advanced liver fibrosis (hazard ratio [HR], 3.4; 95% CI, 1.2-9.6), clinically significant portal hypertension (HR, 2.1; 95% CI, 1.2-3.8), and level of albumin below 3.5 mg/dL (HR, 4.1; 95% CI, 2.3-7.6), adjusted for SVR achievement as a time-covariable. Attaining an SVR reduced the risk of liver decompensation (HR, 0.3; 95% CI, 0.1-0.8; P=.016) and de novo HCC (HR, 0.2; 95% CI, 0.1%-0.8%; P=.02) in the overall cohort.Treatment of HCV infection with DAAs significantly reduces the risk of new liver-related complications and should be offered to all patients, regardless of disease stage. www.clinicaltrials.gov no: NCT03775798.