Chronic hepatitis C virus (HCV) infection is associated with neuropsychiatric changes. Also, patients with cirrhosis may develop overt or minimal hepatic encephalopathy. Sustained virological response (SVR) with direct-acting antiviral agents (DAAs) may improve the neuropsychiatric manifestations and quality of life (QoL). Consecutive patients (with and without cirrhosis, all genders and aged 18-65years) with hepatitis C were assessed at enrolment and at 12weeks after therapy completion for mood (Beck's Depression Inventory [BDI]), anxiety (generalized anxiety disorder [GAD-7]), QoL (SF-36 ver.2) and computer-based tests for number connection (NCT), visual memory, Stroop test and reaction times. We recruited 385 viraemic chronic HCV patients (76.1% male, 21.0% cirrhotic, mean age 39.4±14.2years, 59.3% genotype 3, mean HCV RNA load 5.8log). Overall SVR-12 rates were 90.6%, with cure rates 87.6% and 91.4% in patients with and without cirrhosis, respectively. Patients who achieved SVR-12had mean percentage reduction in BDI (11.3%, p=.000), GAD (8.6%, p=.001) and Stroop test (58.4%, p=.001), with improved NCT (1.7%, p=.001), visual memory (13.7%, p=.001) and digit span (23.8%, p=.002). On multivariate logistic regression, adherence (OR, 17.5 [95% CI 2.80-110.50], p=.000), high ALT (OR 1.02 [95% CI 1.00-1.05]), and BDI score (OR 1.73 [95% CI 1.42-3.26] p=.039) predicted cure. SVR-12 was associated with improved visual memory ≥5.5 (AUC-0.708; sensitivity 62.5%, specificity 63%, p=.000) and % correct Stroop test responses >26.6% (AUC-0.918, sensitivity 94.4% specificity 80.4%, p=.000). In conclusion, given the cumulative evidence of the safety of DAAs and efficacy of improving cognitive and neuropsychological and quality-of-life outcomes irrespective of age and gender, as shown in our study, future recommendations should focus on integrated universal HCV care to enable HCV elimination.