OBJECTIVES: The study aimed to assess the cost-effectiveness of abatacept, adalimumab, etanercept, infliximab and golimumab in combination with methotrexate (MTX) in patients with Rheumatoid Arthritis (RA) who fail treatment with MTX from the Spanish Health System point of view.  METHODS:  A Markov model was developed in MS Excel software based on a meta-analysis and an economic evaluation performed by the Canadian Agency for Drugs and Technologies in Health. The model included 7 health states: therapy initiation; clinical response according to ACR 50 (American College of Rheumatology (ACR) response criteria); clinical response according to ACR 20; no response; severe adverse events; change therapy; and death. The cost (€ in 2013) and effectiveness (life years (LY) in ACR 50) for each treatment option were collected over a 5-year time horizon using a cohort of 1,000 Spanish patients with a mean age of 52 years. The structure and the clinical assumptions of the analysis were validated in a Delphi panel composed of 3 clinical experts in order to adapt the model to the Spanish setting. Pharmacological costs were estimated using the ex-factory price discounting the corresponding deduction according to Royal Decrees. Univariate and probabilistic sensitivity analyses were performed. RESULTS: The Incremental Cost-Effectiveness Ratio of adalimumab, etanercept, golimumab, infliximab and abatacept came to 13,374€, 20,943€, 27,740€, 32,997€ and 41,704€, respectively. The results of both sensitivity analyses showed the robustness of the model. CONCLUSIONS: The present analysis found adalimumab in combination with MTX to be the most cost-effective biological drug for patients with RA who failed treatment with MTX alone in terms of LY in ACR 50 response. These results are in line with the Spanish clinical guidelines for RA which recommend the use of tumor necrosis factor inhibitors as first-line treatment after failure with disease-modifying antirheumatic drugs.