OBJECTIVES: Following broadening of the EMEA license for first-line treatment of previously untreated patients with chronic lymphocytic leukaemia (CLL) with rituximab added to chemotherapy, we evaluated the cost-effectiveness of rituximab in combination with commonly used chemotherapy regimen of fludarabine plus cyclophosphamide (R-FC) versus fludarabine plus cyclophosphamide (FC) from the perspective of the Spanish national healthcare system. METHODS: A three stage Markov model including progression-free survival (PFS), progression state and mortality was developed using published results from the randomized clinical trial CLL-8 evaluating PFS in patients with CLL. Rates of disease progression were derived from a Weibull model, mortality rates were obtained from Kaplan-Meier and Spanish age-specific mortality tables. Patient elicited utilities were applied to PFS and progressed health states. The cost of drugs, supportive care, and quality-adjusted life years (QALY) were estimated over a period of 10 years, the median survival for CLL, and discounted at 3.5 per annum. Univariate and probabilistic (Monte Carlo simulation) sensitivity analysis were performed. RESULTS: The addition of rituximab to chemotherapy increased life-years gained (LYG) and QALYs by 0.669 and 0.617 years per patient, respectively, compared to chemotherapy alone. The incremental cost per LYG and QALY gained was €17,726 and €19,220, respectively. Cost-effective results were obtained with Monte Carlo simulation. Univariate sensitivity analyses indicated the results were robust, and most sensitive to time horizon, with a threshold value at year 7, from which the R-FC regimen is cost-effective. CONCLUSIONS: The model demonstrated that the addition of rituximab to fludarabine plus cyclophosphamide (FC) regimen increased life and quality-adjusted life expectancy and is a cost-effective first-line treatment option for patients with chronic lymphocytic leukaemia.