OBJECTIVES: Rituximab (MabThera®, RTX) is a novel genetically engineered anti-CD20 therapeutic monoclonal antibody for rheumatoid arthritis (RA) patients in which anti-TNFα therapies failed. The aim of this study is to assess the cost-effectiveness of RTX relative to current therapy for RA patients not responding adequately to anti-TNFα therapies. METHODS: Decision-analytic model employing a Monte Carlo micro-simulation of a Markov process with cohorts of 10,000 RA patients who had responded inadequately to one anti-TNF therapy. The model estimates lifetime HAQ progression, QALYs and direct costs based on ACR response rates for sequences of treatments, available epidemiological data from observational studies and baseline characteristics from both the REFLEX phase III trial and VACAR study. This observational trial with 244 RA patients in Spain yield functions converting HAQ scores into utilities (HUI3=0.9527-0.2018*HAQ and EQ-5D=0.9567-0.309*HAQ). Economic outcomes included costs (2008 €) for therapy (comprising of: drug costs, administration and monitoring), and those related to disease progression, palliative care and reduced productivity. Both costs and benefits were discounted at an annual rate of 3.5%. RESULTS: Annual average treatment costs were €7,469 for RTX+MTX, €13,954 for adalimumab, €12,968 for etanercept, and €9,811 for infliximab. Added to existing therapies, RTX would lead to a gain of 0.523-0.781 QALYs (when baseline characteristics from REFLEX study, 0.619-0.908 for VACAR population) with an estimated ICER of €13,593-21,703 per QALY gained (€11,143-17,899). CONCLUSIONS: Availability of RTX for Spanish RA patients 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 diminish. If utility functions from VACAR study are used with REFLEX population, QoL results are robust when compared to common utility functions in RA literature (Bansback et al 2004, Hurst et al 1997, Kobelt et al 1999).