OBJECTIVES The aim of this study is evaluation of the effectiveness and cost-effectiveness of using rituximab as first line of treatment for patients with refractory rheumatoid arthritis in comparison to continuing conventional DMARDs, from a perspective of health service governors. METHODS A systematic review was implemented through searching PubMed, Scopus and Cochrane Library. Quality assessment was performed by JADAD questionnaire. After meta-analysis of ACR (American College of Rheumatology) index results, QALY (Quality Adjusted Life Years) gained were calculated through mapping ACR index to HAQ (Health Assessment Questionnaire) and utility index. To measure the direct and indirect medical costs, a set of interviews with patients were applied. Thirty two patients were selected from three referral rheumatology clinics in Tehran with definite diagnosis of refractory rheumatoid arthritis one year before, and treatment regimen of either rituximab or DMARDs within last year. Incremental cost-effectiveness ratio were calculated for a period of six months for base case and generic rituximab scenario. Three fold of GDP (Gross Domestic Product) per capita was considered as threshold of cost-effectiveness. RESULTS Four studies were eligible to be considered in this systematic review. Total risk difference of 0.3 for ACR20 criteria, 0.21 for ACR50 and 0.1 for ACR70 were resulted from meta-analysis. Also mean of total medical costs of patients for 24 weeks were $3985 in rituximab group and $932 for DMARDs group in the base case analysis. Thus, the incremental cost per QALY ratio will be $45900 to $70223 in the base case, and $32386 to $49550 for generic scenario, while the threshold of cost-effectiveness was $21684. CONCLUSIONS Rituximab cannot be considered as cost-effective for the treatment of patients with refractory rheumatoid arthritis in Iran.