BACKGROUND: Chronic kidney disease (CKD)-associated pruritus is a condition that strongly impacts CKD patients and is associated with increased morbidity/mortality, and worse health-related quality of life (HRQoL). Difelikefalin is currently the only drug approved in Europe specifically for treating moderate to severe CKD-associated pruritus in patients undergoing hemodialysis. The KALM-1 and KALM-2 trials showed better efficacy of difelikefalin vs placebo and best supportive care. The aim of this study was to investigate the cost-effectiveness of difelikefalin according to the Italian National Health Service (NHS) perspective. METHODS: A cohort model represented by four health states (No, Mild, Moderate, and Severe pruritus) was adapted to the Italian setting. The model used data from the KALM-1 and -2 trials for efficacy, integrated with other publications for HRQoL estimations. To assess the cost of disease management, a recent Italian publication on CKD-associated pruritus was used and a price of €27 per difelikefalin vial was assumed. The base case analysis over a 15-year time horizon, and an additional 10-year scenario analysis, were established. Additionally, both deterministic univariate analysis and probabilistic multivariate sensitivity analyses were developed. Discount rates of 3% were applied. An acceptability threshold of 40,000 €/quality-adjusted life-year (QALY) was considered. RESULTS: The results show that difelikefalin plus best supportive care is cost-effective vs best supportive care alone, with an incremental cost-effectiveness ratio, in the base case, of €35,823/QALY. Both the scenario and sensitivity analyses confirmed the strength of the results. CONCLUSIONS: Difelikefalin was found to be a cost-effective treatment for the Italian NHS. These results support its reimbursement and its inclusion in routine clinical practice.