Objectives: The aim of this study was to estimate the total annual direct costs incurred by the National Health Service for the management and treatment of CSCC and advanced CSCC patients in Italy. Methods: An incidence-based cost of illness (COI) model was developed to estimate direct costs associated with the treatment and management of CSCC patients in Italy. The identified treatment pathway was validated with a team of clinical experts and was distinguished between resectable CSCC and locally advanced CSCC or metastatic CSCC. Treatments costs were obtained through the analysis of the National Hospital Discharge Database (HDD) for the years 2015-2018; monitoring and terminal care costs were obtained from national tariffs of outpatient care service and from the literature respectively. Results: Associating the estimated costs for each phase of the treatment pathway with the proportion of patients present in each phase, the COI model estimated an annual economic burden of about € 25.9 million for the management and treatment of patients with CSCC in Italy, € 2.7 million of which were associated to patients with advanced CSCC. The average cost per patient with advanced CSCC was higher compared to that of patient with resectable CSCC (€ 4,490 vs € 2,236 respectively). Conclusions: Our analysis showed that advanced CSCC patients are associated with a higher average cost than patients with resectable CSCC.