Background and Objective: Ibrutinib has recently been approved in Europe for Waldenstrom Macroglobulinemia (WM) in symptomatic patients who have received at least one prior therapy, or in first-line treatment for patients unsuitable for chemo-immunotherapy. The aim of the study is to estimate the incremental cost-effectiveness ratio (ICER) of ibrutinib in relapse/refractory WM, compared with the Italian current therapeutic pathways (CTP). Methods: A Markov model was adapted for Italy considering the National Health System perspective. Input data from literature as well as global trials were used. The percentage use of therapies, and healthcare resources consumption were estimated according to expert panel advice. Drugs ex-factory prices and national tariffs were used for estimating costs. The model had a 15-year time horizon, with a 3.0% discount rate for both clinical and economic data. Deterministic and probabilistic sensitivity analyses were performed to test the results strength. Results: Ibrutinib resulted in increased Life Years Gained (LYGs) and increased costs compared to CTP, with an ICER of euro52,698/LYG. Sensitivity analyses confirmed the results of the BaseCase. Specifically, in the probabilistic analysis, at a willingness to pay threshold of euro60,000/LYG ibrutinib was cost-effective in 84% of simulations. Conclusions: Ibrutinib has demonstrated a positive cost-effectiveness profile in Italy.