Abstract Background Chronic hepatitis C virus (HCV) infection is a major global public health problem. This study investigated the evolving landscape of HCV in Tuscany (Italy) from 2015 to 2022, considering demographic shifts, clinical profiles, treatment regimens, and outcomes. Methods The study was conducted in order to characterize HCV-positive patients who started treatment between 2015 and 2022 in Tuscan prescribing centers. The study was part of OPT-HepaC, a project funded by Regional Health Service. Data on demographics, clinical history and outcomes were collected. Three different temporal eras were analysed: the period before andfter the universal availability of direct-acting antivirals (DAA) and the COVID-19 era. Treatment’s effectiveness was evaluated by the Sustained Virological Response (SVR12), assessed 12 weeks after the end of treatment. Outcomes included SVR12, non-SVR12 and lost to follow-up (LTFU). ANOVA, Kruskal-Wallis test and multinomial logistic regression were used for statistical analysis. Results 6882 HCV patients (age: 58.88±14.21) were treated by the centres participating at the study. Males (56.4%) and Italian (91.8%) were predominant. Sociodemographic and variable characteristics vary across the time. While the overall SVR12 remained stable over time (χ2(2)=0.357, p = 0.837), the LTFU rate significantly increased during the COVID-19 era. Facilitating factors for the non-SVR12 and LTFU outcomes were male gender (Odds Ratio (OR)=2.134, p = 0.006)/cirrhosis (OR = 1.713, p = 0.040)/HIV co-infection (OR = 3.251, p = 0.005) and DAA treatment of third generation (OR = 4.187, p = 0.006), respectively. Conclusions The study provides a comprehensive view of the HCV landscape, highlighting demographic changes, treatment regimens and outcomes. The COVID-19 pandemic affected service delivery, delaying HCV diagnosis/treatment and influencing the LTFU rate. Despite challenges, the region maintained high SVR12 rates, emphasizing the importance of sustained efforts in HCV care. Key messages • The study highlights the dynamic nature of HCV management in Tuscany. • The study emphasises the need for continuous adaptation to public health challenges, providing insights for future public health strategies.