OBJECTIVES: Waldenström macroglobulinemia (WM) is a B-cell lymphoproliferative disorder characterized by histological bone marrow evidence of lymphoplasmacytic cells and an immunoglobulin M-monoclonal gammopathy. It is a rare disease of the elderly that, although indolent, remains incurable, and most patients succumb to multiple relapses. Ibrutinib has recently been approved for symptomatic WM 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 current therapeutic pathways (CTP) used in Italy (i.e. bortezomib + rituximab, rituximab + CHOP, bortezomib + dexamethasone + rituximab, dexamethasone + rituximab + cyclophosphamide, bendamustine + rituximab, fludarabine + cyclophosphamide + rituximab). METHODS: A Markov model, previously developed to estimate the costs and outcomes associated with WM treatments, was adapted to the Italian setting, considering the National Health System (NHS) perspective. Input data from national and international literature as well as global trials (2007–2015), were used. The percentage use of ibrutinib and other WM therapies, as well as healthcare resources consumption were estimated according to an expert panel. Drugs’ ex-factory prices and national tariffs (inpatient and outpatient) were used in order to estimate the mean yearly cost of the compared treatments. As suggested by the expert panel, the model had a 15-year time horizon. A 3.0% discount rate for both clinical and economic data was used. RESULTS: Treatment with ibrutinib resulted in increased Life Years (LYs; +3.0) and increased cost (+€153,297) compared to CTP. ICER/LY comparing ibrutinib versus CTP was €51,099. In the probabilistic sensitivity analysis, at a willingness to pay threshold of €60,000/LY (threshold considered acceptable for an Italian payer), ibrutinib was cost-effective in 84% of simulations. CONCLUSIONS: Ibrutinib is a cost-effective therapy in WM patient management.