Rituximab (RTX), is a new and unique selective B-cell therapy for rheumatoid arthritis (RA) patients who respond inadequately to anti-TNF therapies. OBJECTIVES: We determined the cost-effectiveness of introducing RTX in Spain. METHODS: Our cost-effectiveness model simulates a real-life Spanish treatment sequence for 10,000 RA patients who had responded inadequately to one anti-TNF therapy. We used ACR response rates for RTX and current treatment options, available epidemiological data from observational studies and baseline characteristics from the REFLEX study. The model estimated the incremental cost per QALY gained, with RTX as either a new or alternative treatment over each patient's remaining lifetime, assuming time-on-treatment for biological agents (in combination with methotrexate) of up to 4.25 years. QALYs came from a disease severity measure (HAQ score). Costs included (2004-5 EURO) drug costs (including administration and monitoring) and costs related to disease progression, palliative care, and reduced productivity (indirect costs). Costs and benefits were discounted at 3.5% per annum. RESULTS: Annual average treatment costs were €7,431 for RTX + MTX, €14,072 for adalimumab, €13,067 for etanercept, and €9,823 for infliximab. Added to existing therapies, RTX would lead to a gain of 0.632 QALYs at an additional total direct medical cost of €11,550 over each patient's lifetime. The corresponding incremental cost-effectiveness ratio (ICER) of RTX was €18,261 per QALY gained. Corresponding ICERs for drug therapy and total costs were €19,597 and €15,546 per QALY gained, respectively. Used in place of etanercept as second-line biologic DMARD, RTX + MTX were associated with lifetime drug cost-savings of over €17,000. CONCLUSIONS: Adding RTX to the pool of available treatment options for Spanish patients with RA who respond inadequately to anti-TNF therapy results in a favourable incremental cost per QALY gained. When RTX is replacing another biologic DMARD, the average annual drug therapy costs can be lowered.