OBJECTIVES: Clinical studies such as REFLEX established the efficacy of rituximab (RTX) in patients with rheumatoid arthritis (RA) who have had an inadequate response to anti-TNF therapy. This analysis evaluated the cost-effectiveness of treating such patients with RTX across different EU countries. METHODS: Our cost-effectiveness model assessed RA treatments in a real-life setting based on practices in Germany, Italy, Spain, France, and the UK. The model is based on ACR response rates for RTX and current treatment options (adjusted for the different study populations), complemented with epidemiological data from observational studies. It simulates a cohort of 10,000 patients who have failed to respond to anti-TNF therapy. Baseline patient characteristics were from the REFLEX study. For each country, the cost-effectiveness of providing RTX either as an additional treatment or an alternative to a second-line biologic DMARD was examined using a treatment duration for biological therapy (in combination with methotrexate) of up to 4.25 years. QALYs were mapped from a disease severity measure (HAQ score) and resource utilization data were UK or German registry data. The model included costs related to drug therapy (including administration and monitoring), palliative care and reduced productivity (indirect costs) (2004–5 Euros [€]). Costs and benefits were discounted at 3.5% per annum. RESULTS: Using RTX resulted in lower average annual cost compared to any of the anti-TNF treatments. The cost per QALY (direct medical cost) was in the range of €18,000 to €23,000 across all health care systems. When RTX is replacing a treatment option in the current treatment sequence, average annual treatment costs can be reduced. CONCLUSIONS: This pan-European analysis shows that adding RTX to the therapeutic armamentarium for patients with RA who respond inadequately to anti-TNF therapy is highly cost-effective, with an incremental cost per QALY gained that is favourable compared to other disease-modifying, biological therapies.