Abstract: Introduction Rheumatoid arthritis (RA) is a chronic inflammatory disease which affects joints and can lead to deformity of proximal organs due to erosion [1]. Prevalence of RA is ranging from 0.3 to 2.1 % in different societies [2]. As reported before, 0.33 % of urban population and 0.19 % of rural population are affected with RA in Iran [3]. With over 77 million population [4], it can be estimated that about 42,000 people in rural area and over 181,000 in urban area are suffering from RA in this country, which includes about 20–40 thousands of disabled individuals. Although still no exact cause has been identified for this disease, the role of immune inflammatory factors such as IL-1 and TNF alpha is almost apparent [5]. That is why new biologic drugs including anti-TNF (infliximab, Abstract The aim of this study was to evaluate the effectiveness and cost-effectiveness of using rituximab as first line for patients with refractory rheumatoid arthritis in comparison with continuing conventional DMARDs, from a perspective of health service governors. A systematic review was implemented through searching PubMed, Scopus and Cochrane Library. Quality assessment was performed by Jadad scale. After meta-analysis of ACR index results, QALY gain was calculated through mapping ACR index to HAQ 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 in the year before and treatment regimen of either rituximab or DMARDs within last year. Incremental cost-effectiveness ratio was calculated for base case and scenario of generic rituximab. Threefold of GDP per capita was considered as threshold of cost-effectiveness. Four studies were eligible to be considered in this systematic review. Total risk differences of 0.3 for achieving ACR20 criteria, 0.21 for ACR50 and 0.1 for ACR70 were calculated. Also mean of total medical costs of patients for 24 weeks were $3985 in rituximab group and $932 for DMARDs group. Thus, the incremental cost per QALY ratio will be $45,900–$70,223 in base case and $32,386–$49,550 for generic scenario. Rituximab for treatment of patients with refractory rheumatoid arthritis is not considered as cost-effective in Iran in none of the scenarios. Keywords Rheumatoid arthritis · Cost-effectiveness · Rituximab · Iran