OBJECTIVES: Purpose of the study was to conduct a cost-efficacy analyses between three combinations of Tumor Necrosis Factor-Alpha agents used in treatment of rheumatoid arthritis. The study compared adalimumab plus methotrexate (ADAL+MTX), infliximab plus methotrexate (INFL+MTX), etanercept plus methotrexate (ETAN+MTX), with methotrexate (MTX) monotherapy (control). METHODS: The study was conducted from the patients' perspective. Costs calculated for a period of one year included direct medical costs (drug acquisition costs, monitoring costs, and adverse drug event costs) and indirect costs (estimated using human capital approach). All costs were calculated in 2007 dollars and adjusted using a discounting factor of 3%. Outcome of therapeutic options was measured using the American College of Rheumatology criteria for 20% improvement (ACR20 criteria). Data was obtained from a comprehensive literature review using PubMed, Medline, and Cochrane library. Efficacy values were obtained from published randomized clinical trials. A decision tree analyses was conducted followed by one-way and two-way sensitivity analyses. Costs and efficacy values associated with therapeutic options were varied in the sensitivity analyses. RESULTS: The probability of achieving ACR20 response for ETAN+MTX, ADAL+MTX, INFL+MTX, and MTX were 85.5%, 65.95%, 61.26%, and 39.94%, respectively. The probability of an adverse drug event occurrence for ETAN+MTX, ADAL+MTX, INFL+MTX, and MTX were 14.0%, 6.5%, 7.9%, and 9.5%, respectively. The analysis revealed that ETAN+MTX option was the most cost-efficacious, with an annual cost of $52,369 to the patient. The annual cost savings with ETAN+MTX combination use would be $19,318. Annual costs of ADAL+MTX, INFL+MTX, and MTX monotherapy were $79,058, $68,932, and $67,071 respectively. Results were robust to both one-way and two-way analysis. CONCLUSIONS: Etanercept plus Methotrexate combination therapy was a better option based on the ACR 20 outcome measure considered. An analysis using real world data and/or a prospective head-to-head comparison study could provide better conclusive evidence for decision-makers.