OBJECTIVES: To compare the effectiveness of oral leflunomide (Arava®) and subcutaneous metotrexate (Metoject®) using the Number Needed to Treat (NNTs), a measure supported by the Evidence Based Medicine approach. The effectiveness results have been combined with Spanish annual costs to assess the economic impact of these treatments. METHODS: An event has been defined as non-responder patient according to ACR20 and ACR50 criteria with each of the drugs compared. NNTs calculated as the inverse of the Absolute Risk Reduction, have been derived using results according to intention-to-treat from a randomised controlled trial (US310) comparing 20mg daily of leflunomide with 7.15-15 mg weekly of metotrexate, administered during 1 year. Considered annual treatment costs related with the costs of the drug administered the consultations and lab tests performed for routine monitoring, according to the information provided by the manufactures in their summary of product characteristics. Unitary costs have been obtained from Spanish cost databases. RESULTS: Using the ACR20 criteria NNTs with leflunomide and metotrexate SC are 4 (95% CI 2.56-7.71) and 5 (95% CI 3.03-14.3) respectively. Using the ACR50 criteria NNTs are 4 (95% CI 2.72-6.54) and 7 (95% CI 4.03-19.3). The annual cost of each treatment per patient-year (drugs and monitoring) equals 1793.3€ in case of leflunomide and 2149.2€ for metotrexate SC. Combining these results the cost of a controlled patient according to ACR20 amounts 7173€ for leflunomide and 10,746€ for metotrexate SC. Results according to ACR50 equals 7173€ and 15044€ respectively. CONCLUSION: From the Spanish National Health System perspective and effectiveness measured as respondent according to ACR20 the use of leflunomide for patients with Rheumatoid Arthritis could achieve important cost savings compared with the administration of metotrexate SC. The savings could be even more important when the ACR50 response criteria are considered.