OBJECTIVES:  Over the period 2014-2015, the advent of DAAs generated widespread concern, particularly within the Italian setting, characterised by continuous spending review actions. The study aimed at estimating the budget impact of the introduction of novel drugs approved in May 2015, compared with the historical situation based on the different treatment options available prior to May 2015, assuming the Lombardy Region Health Service (RHS) perspective. METHODS: A budget impact analysis (BIA), representing Lombardy Region HCV healthcare expenditure evolution over three years, was developed, considering the overall HCV and HIV/HCV population. Patients’ previous medical history, degree of liver fibrosis, genotypes, achievement of sustained virological response (SVR) and direct healthcare total costs were the model input variables. Data were collected from scientific evidence, regional legislation and administrative information of two Lombardy Region Hospitals: Valle Olona and Fatebenefratelli Sacco. RESULTS: Two different populations were hypothesised: i) the population related to the regional spending cap (N=13,658), and ii) the population related to the organizational and productive cap (starting from the Regional Decree 7826, 2015, N=31,722). At the 36 month-horizon of the base-case scenario for market penetration, the introduction of the novel therapies could lead to i) a substantial increase in HCV and HIV/HCV patients achieving a SVR (+20%) and ii) significant economic savings to the RHS (-6.64%/-7.15%), even considering the adverse events’ impacts. The initial investment in innovative therapies would be recovered within 24 months, generating outcomes improvement and economic benefits for the RHS, which could be consolidated in time. CONCLUSIONS: The results suggest the need of attentive healthcare planning that is able to concentrate the therapeutic alternatives and precisely forecast the HCV population, thus leading to: i) a reduction in health expenditure, ii) ensuring a better virological control, and iii) guaranteeing the best cost-effective result with a greater ledipasvir/sofosbuvir consumption.