OBJECTIVES: To compare, in the Spanish setting, the annual costs associated with the management of adult patients with rheumatoid arthritis using oral leflunomide (Arava®) or a new presentation of metotrexate (Metoject®, prefilled syringes). METHODS: Due to the absence of any randomized controlled trial that had showed significant differences in effectiveness between leflunomide and metotrexate a cost-minimization analysis has been performed under the Spanish societal perspective. Data about effectiveness and dose of drugs administered were obtained from the clinical trial US310, a 12 months-randomised controlled trial which compares head-to-head 20mg daily of leflunomide versus 7.15-15mg weekly of metotrexate. Use of other medical resources like lab tests and consultations related with drug monitoring were derived from the manufacturers' summary of product characteristics. Patient time and productivity time lost were derived from other published studies and economic evaluations. RESULTS: Annual drug costs with leflunomide and prefilled syringes of metotrexate are 1,112.52€ and 1,438.91€ respectively. Annual monitoring costs amount 680.76€ and 710.26€ respectively. Other direct medical costs equal up to 677€ and 542€ while indirect costs amount 862€ and 577€ respectively. CONCLUSION: Metoject®, a new presentation of metotrexate has been recently launched in Spain. The significant rise in price of Metoject® compared with other presentations of metotrexate justifies performing an economic evaluation comparing it with the administration of oral leflunomide (Arava®). Arava® has lower drug and monitoring related costs than Metoject®, while not statistically significant differences in other direct and indirect costs have been observed between the treatments.