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Aim of the study: The aim of this overview was to evaluate the efficacy of sofosbuvir/velpatasvir (SOF/VEL) combination in a real-life setting, with particular regard to treatment-experienced individuals. Material and methods: Seventy-five consecutive patients who were treated with SOF/VEL, completed the 12-week follow-up and had sustained virologic response (SVR) evaluated were included in the analysis. Out of them, 60 (80%) patients were treatment-naïve and 15 (20%) were treatment-experienced. Results: SVR rates reached 89.4% (66/75) in the whole study group and were comparable irrespective of the fibrosis stage or HCV genotype. However, a significant difference in treatment efficacy between treatment-naïve and treatment-experienced individuals was observed, with SVR rates of 98.3% (59/60) and 46.7% (7/15), respectively (p < 0.0001). Conclusions: Further studies including large real-life cohorts of treatment-experienced patients treated with SOF/VEL are warranted to elucidate the real efficacy of this regimen as a retreatment option.