OBJECTIVES: Rituximab (RTX), a unique selective B-cell therapy, is a new option for rheumatoid arthritis (RA) patients who respond inadequately to anti-TNF therapies. This study reports a cost-effectiveness analysis modelling the introduction of RTX in Italy. METHODS: We used ACR response rates (adjusted for differences in study populations), plus observational data from EU registries and simulated real-life treatment for 10,000 RA patients who had responded inadequately to anti-TNF therapy, using baseline patient characteristics from the REFLEX study. We assumed an average treatment duration for biological therapy (in combination with methotrexate) of up to 4.25 years over the patient's remaining lifetime. QALYs were mapped from a disease-severity measure (HAQ score) and based on registry data. Relevant costs included (2004–5 Euros [€]) drug costs (including administration and monitoring) and those related to reduced productivity (indirect costs). We assessed RTX as either a new treatment step or instead of adalimumab. RESULTS: Average annual treatment costs were €8,796 for RTX + MTX, €14,133 for adalimumab, €14,406 for etanercept, and €9,950 for infliximab. Compared with the current treatment sequence, RTX + MTX as a new treatment step produced a gain of 0.677 QALYs at an incremental total medical cost of €12,355 over the lifetime of each patient – an incremental cost-effectiveness ratio (ICER) of €18,259 per QALY gained. The incremental cost per QALY for drug therapy or total (direct + indirect) cost was €19,241 and €13,621. RTX used instead of adalimumab produced a similar QALY gain, but resulted in a total direct medical-cost saving of €11,389 over the patient's lifetime. CONCLUSIONS: RTX offers a highly acceptable incremental cost per QALY gained for Italian patients with RA who respond inadequately to anti-TNF therapy and the possibility of either treating more patients within an existing budget or reducing the overall treatment cost for RA patients.