Objective: To investigate the cost-effectiveness of biological response modifiers in patients with moderate to severe rheumatoid arthritis who have experienced an inadequate response to methotrexate Methods: A decision analytic model was constructed to estimate the costs and effectiveness of adalimumab, anakinra, etanercept, and infliximab alone or in combination with methotrexate for 6 months. Effectiveness was measured by American College of Rheumatology response criteria (ACR20) as reported in published clinical trials. Costs included direct medical costs (including medication, monitoring, and adverse event costs) and indirect costs due to impaired work productivity. Extensive univariate and probabilistic sensitivity analyses were performed Results: In the base case, costs for 6 months of therapy were lowest for etanercept monotherapy ($22,487) and highest with the combination of infliximab and methotrexate ($24,807). For monotherapy and combination therapy regimens, etanercept was the least expensive option and most effective option compared to other treatments, although differences in cost and effectiveness across treatments were relatively small. After eliminating dominated options, etanercept + MTX therapy increased the probability of achieving an ACR 20 by 7% points and increased total costs by $199 over etanercept monotherapy agent, resulting in an incremental cost-effectiveness ratio of $2843 per additional response. The incremental cost-effectiveness of combination therapy compared to monotherapy was not markedly altered in sensitivity analyses Conclusion: Findings from this study suggest that there are relatively small differences in cost and effectiveness across biological response modifiers. Combination therapy with biological response modifiers appears to provide an increase in response compared to methotrexate alone, but at a cost. Whether combination therapy can be considered cost-effective depends on the value attached to achieving ACR response