OBJECTIVES: Rituximab has recently received European approval for its use in combination with any chemotherapy. The aim of this study is to evaluate the cost-effectiveness of rituximab added to the most commonly used chemotherapy regimens, performed from the Spanish National Health System perspective. METHODS: We developed a Markov model based on 3 randomized controlled clinical trials comparing the addition of rituximab to chemotherapy regimens of CVP; MCP or CHOP vs chemotherapy alone, in patients with advanced follicular lymphoma. Progression-free survival (PFS) and overall survival were the endpoints evaluated in these trials. Rates of disease progression were derived from the PFS Kaplan-Meier curves, mortality rates were obtained from the Scotland-Newcastle Lymphoma Group database and Spanish age-specific mortality tables; resource consumption data was based on a local expert panel questionnaire and patient utilities to account for quality of life were applied to the PFS and progressed health states. Medication and supportive care costs, and quality-adjusted life years (QALYs) were estimated over 10 years and discounted at 3.5%. Univariate and probabilistic sensitivity analysis were performed. RESULTS: The addition of rituximab to chemotherapy increased QALYs by 0.795, 1.129 and 0.971 years for CVP, MCP and CHOP, respectively, compared to chemotherapy alone. The incremental cost per QALY gained was €10,190, €6,092 and €7,855, for CVP, MCP and CHOP, respectively. The incremental cost per life year gained was €10,168, €6,348 and €8,190, for CVP, MCP and CHOP, respectively. Sensitivity analyses indicated the results were robust, and most sensitive to the duration of treatment effect and time horizon. CONCLUSIONS: The addition of rituximab to any of the chemotherapy regimens evaluated, was estimated to increase quality-adjusted life expectancy, and be a highly cost-effective treatment option for patients with advanced follicular lymphoma.