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Background: New direct-acting antiviral drugs can eradicate hepatitis C virus (HCV) infection in over 90% of patients and can even reduce the risk of complications in advanced fibrosis/cirrhosis. The aims of this study were to evaluate (1) changes in fibrosis during and after antiviral treatment and (2) incidence of hepatocarcinoma and mortality in various fibrosis stages. Methods: This is a longitudinal monocentric prospective study. Blood and instrumental examinations were evaluated at baseline, at the end of therapy, and 1 and 2 years following treatment. Results: Two hundred and ninety-six patients with chronic HCV were evaluated, of whom 115 were experienced, 181 were treatment-naïve, and 2 had previous hepatocellular carcinoma (HCC) and were therefore excluded from the study. At baseline, stiffness values were 13.46 ± 9.97 kPa. Out of the 294 HCV patients enrolled, 100 had lymphoproliferative disorders and were evaluated separately. This group of patients showed stiffness values pertaining to the F0-F2 group (mean stiffness values were 6.07 ± 1.68 kPa). All other patients showed stiffness values pertaining to the F3-F4 group (mean stiffness values were 17.93 ± 10.23). No statistically significant difference was found between stiffness at baseline compared to the end of treatment (EOT), while significant differences were found between the baseline, 1 year ( p  = .05), and 2 year follow-ups ( p  < .01). Significant differences were found between baseline and EOT, as well as 1 and 2 years after the end of treatment ( p  < .001) in the F3-F4 group. Four out of 140 patients with baseline cirrhosis developed HCC during the post-treatment follow-up, 1 of whom died. Conclusions: Non-invasive methods provide important prognostic information, particularly concerning the observed regression of fibrosis and could be extremely useful for monitoring patients with long life expectancies after direct-acting antiviral treatment.