OBJECTIVES: Using rituximab for patients with rheumatoid arthritis who are refractory to conventional and/or biologic “disease modifying anti-rheumatic drugs” (DMARDs) is common choice of therapy in Iran. We evaluated the effectiveness and cost-effectiveness of using rituximab for these patients in comparison to continuing conventional DMARDs, from a perspective of health service governors. METHODS: A systematic review was implemented through searching MEDLINE, Scopus and Cochrane Library. Inclusion criteria were being an RCT on rituximab, for refractory rheumatoid arthritis patients, and with a control group of DMARDs. Included articles were qualified by JADAD questionnaire. Risk Difference and CI were calculated and heterogeneity was tested by the Cochran Q test. To measure the direct and indirect medical costs, a set of interviews with patients were applied. Thirty two patients were selected from three referral clinics in Tehran with definite diagnosis of refractory rheumatoid arthritis in the year before, and treatment regimen of either rituximab or DMARDs within last year. Incremental cost-effectiveness ratio was calculated using mean of costs for 6 months period and risk difference, with a scenario and sensitivity analysis. RESULTS: From 1875 related articles, 4 studies were eligible to be considered in this systematic review. Results of meta-analysis showed homogeneity of all 4 studies and a total risk difference of 0.3 for ACR20 criteria, 0.2 for ACR70WR, and 0.37 for EULAR criteria of response.  Also mean of total medical costs of patients for one year were $7957 in rituximab group and $1861 for DMARDs group. Hence, the cost-effectiveness ratio will be $10159 per ACR20, $15238 per ACR70WR, and $8237 per EULAR in base case analysis, while in generic rituximab scenario shows a 30% reduction of results. CONCLUSIONS: Rituximab for patients with refractory rheumatoid arthritis does not seem to be cost-effective in Iran, although generic use of this drug can be encouraged.