OBJECTIVES: The aim of this analysis was to evaluate cost consequences of rituximab (RTX) treatment in rheumatoid arthritis (RA) from the payer perspective, in a phase IV open-label study conducted by Clalit Health Services, the largest Israeli HMO, in collaboration with Roche Pharmaceuticals. METHODS: Patients with prior inadequate response to disease-modifying anti-rheumatic drugs (DMARDs) or to both DMARDs and anti-TNFs received the RA RTX regimen (1gx2). The clinical outcome measure was moderate/good EULAR response at 24 weeks. Responding patients were eligible to re-treatment with RTX upon disease exacerbation after a minimum of 48 weeks. Costs of RTX treatment (drug acquisition & administration) were compared to average costs of the spared anti-TNFs (infliximab, etanercept or adalimumab) that would have been provided otherwise to each patient until RTX re-treatment or end of follow-up (FU). Prices are based on Israeli tariff before VAT. RESULTS: A total of 108 patients were enrolled. Sixty-seven DMARDs failures (62%), 41 DMARDs and anti-TNF failures (38%). At time of analysis (January 2008), 89 patients completed a minimum of 24 weeks follow-up (FU). Three dropped out in less than 24 weeks. Median FU: 75 weeks. 35/89 patients (39%) received re-treatment with RTX at a median of 63 weeks. A total of 37/89 patients (42%) were (at time of analysis) still on FU with no other treatment (median FU: 93wks). Average cost in Israel of anti-TNF treatment: NIS1955 (~560$)/week Cost of RTX (2g): NIS34,448 (~$9,840). The total saving per patient (up to data cutoff) results in NIS85,258 (~$24,360). Overall cost saving during this period for 92 patients was NIS7,844 million (~$2,241,120). This sum is still an underestimation since 42% of the patients still require no further treatment, and continue to spare anti-TNF therapy. CONCLUSIONS: From the payer perspective, RTX treatment is a significant cost-saving alternative for patients with RA in the Israeli public healthcare setting.