OBJECTIVES: This study assessed, from a societal perspective, the cost-effectiveness of idelalisib in combination with rituximab versus rituximab monotherapy for the treatment of relapsed/refractory chronic lymphocytic leukemia (CLL). CLL is the most common leukemia in the Western world and is clinically characterized by peripheral blood B-cell lymphocytosis as well as lymphadenopathy, organomegaly, cytopenias and systemic symptoms in advanced stages. METHODS: The cost-effectiveness model adopted a lifetime horizon with three health states: 1) pre-progression; 2) post-progression and 3) death. Patients enter in the model in the pre-progression state and in each cycle (1 week length) may survive without progression; advance to post-progression or die. Remission was not considered in the model: patients in post-progression state remain there until death. Costs and benefits were estimated for the Portuguese setting, and discounted at 5%, as recommended by national guidelines. Univariate and probabilistic sensitivity analyses assessed the robustness of results. Clinical efficacy, safety and utility data were based on published evidence, while survival curves were extrapolated using a Weibull function. Costs estimation was based on Diagnosis Related Group database, national legislation and opinions of an experts’ panel. Model outputs included life years gained, quality-adjusted life years (QALYs), and incremental cost-effectiveness ratios (ICERs).  RESULTS: Survival gains as well as direct medical costs were higher with idelalisib in association with rituximab compared to rituximab monotherapy, but costs related to adverse events and end-of-life care were lower. The ICER was of 32.702€/QALY and 15.935€/LY. Results were sensitive to the discount rates with an undiscounted ICER of 21.942 €. For other parameters univariate analyses ranged between 31.228€/QALY and 34.176 €/QALY. PSA resulted in a median willingness to pay of 34.801€/QALYs or 17.000€/LY.  CONCLUSIONS: Idelalisib plus rituximab in the treatment of relapsed/refractory CLL, compared with rituximab plus placebo, is cost-effective in Portugal.