OBJECTIVES: To determine which tumor necrosis factor-alpha (TNF-alpha) inhibitor is the most cost-effective agent for the treatment of rheumatoid arthritis. METHODS: A Markov model was designed to analyze the cost-utility of certolizumab, etanercept, adalimumab and golimumab versus infliximab (with methotrexate) for the treatment of moderately to severely active rheumatoid arthritis from a U.S. healthcare payer perspective. A cohort of 10,000 patients was simulated using half-cycle correction with a cycle length of three months for a total of five years. The probability of achieving ACR70, serious infections, and hospitalization were based on data from published literature and assumed to follow a beta distribution. Utility scores were based on a published report using a visual analog scale. Costs were adjusted for 2009 U.S. dollars using the medical consumer price index and a discount rate of 3% per annum. Cost and utility scores were assumed to follow a gamma distribution. Probabilistic sensitivity analysis (PSA) was performed to test the robustness of the base-case model. RESULTS: Certolizumab, etanercept, adalimumab and golimumab were dominant compared to infliximab with incremental cost-effectiveness ratios (ICERs) of -$101,377.60, -$137,606.34, -$102,689.18, and -$63,415.60/additional QALY gained, respectively. The cost-effectiveness ratios of certolizumab, etanercept, adalimumab, golimumab, and infliximab were $6325.62, $6467.41, $6595.43, $6903.74, and $7508.16, respectively. Certolizumab resulted in the lowest cost and highest gain in QALYs compared to all comparators. In the PSA, there was a higher proportion of ICERs that were cost-effective with certolizumab (91.06%), etanercept (85.89%), adalimumab (84.67%), and golimumab (79.23%) when compared to infliximab at a willingness-to-pay (WTP) of $60,000. The acceptability curve showed that certolizumab had a higher probability of being cost-effective compared to all other comparators at a WTP of $60,000/additional QALY gained. CONCLUSIONS: At a $60,000 WTP threshold, certolizumab may be the most cost-effective agent for the treatment of rheumatoid arthritis compared to all other TNF-alpha inhibitors.