OBJECTIVES: Treatment options for rheumatoid arthritis (RA) have become diverse in Korea since the introduction of new disease-modifying antirheumatic drugs (DMARDs) such as etanercept. This study aimed to analyze the cost-effectiveness of the major treatment options for methotrexate(MTX)-resistant rheumatoid arthritis in Korea with a time horizon of 6 months. METHODS: A cost-effectiveness analysis was performed to compare 6 major strategies in Korean medical practice for patients with MTX-resistant RA : 1) MTX only, 2)Etanerceptonly, 3)Etanercept +MTX, 4)Cyclosporin+MTX, 5)Leflunomide(20mg) only, 6)Leflunomide(10mg)+ MTX. ACR20 were employed as the measurements of effectiveness. The direct medical costs including medication cost, monitoring and dispensing cost were estimated based on Korean National Health Insurance reimbursement fee schedule. RESULTS: Etanercept monotherapy, Cyclosporin+MTX, and Leflunomide(20mg) monotherapy cost more, but either were not more efficacious or had a high incremental CE ratio than the next most expensive option (i.e., they were dominated). For the least expensive option, Leflunomide(10mg)+MTX, ICER with MTX monotherapy was 2,066,000 Won (Korean currency)/ ACR 20. The most efficacious option, Etanercept+MTX showed the ICER of 29,634,000 Won per ACR20 response. CONCLUSIONS: Leflunomide+MTX was evaluated asa cost effective option for MTX resistant RA in achieving ACR20 over a 6 month period. The most efficacious option, Etanercept+MTX, incurs much higher incremental costs per ACR20 than other options analyzed. It is recommended to prescribe Leflunomide or Etanercept with MTX. In the future, it is also needed to analyses long-term cost effectiveness using Markov modeling and to include indirect cost for RA in order to apply for health insurance policy.