OBJECTIVES: To compare treatment-related risks versus improvements in outcomes in terms of net health benefit (NHB) for 3 treatments for moderate-to-severe rheumatoid arthritis: the anti–tumor necrosis factor drugs (anti-TNFs) adalimumab (ADA) and infliximab (IFX), both in combination with methotrexate (MTX), and MTX alone. METHODS: A simulation model was developed in which a cohort of rheumatoid arthritis patients initiating treatment progressed at 6-month intervals for 10 years or until withdrawal from therapy. NHB, measured in discounted quality-adjusted life-years (QALYs), was calculated for patients receiving ADA+MTX, IFX+MTX, and MTX alone. Outcomes were examined separately for MTX-naïve and disease-modifying antirheumatic drug (DMARD)–failure patients. Treatment benefits were measured by American College of Rheumatology 20, 50, and 70 responses and translated into improvements in Health Assessment Questionnaire Disability Index scores. Risks comprised loss of drug efficacy and adverse events; patients could withdraw from treatment due to either. Benefits and risks were associated with increments and decrements in QALYs, respectively. Data were derived from the published literature and drug prescribing information. RESULTS: MTX-naïve patients on ADA+MTX, IFX+MTX, and MTX alone withdrew after 3.31, 2.46, and 2.71 years and accrued NHBs of 1.40, 1.05, and 1.08 QALYs, respectively. Thus, MTX-naïve patients on ADA+MTX accrued incremental NHBs of 0.35 (P < .05) versus IFX+MTX and 0.32 (P < .05) versus MTX alone. DMARD-failure patients on ADA+MTX, IFX+MTX, and MTX alone withdrew after 3.33, 2.11, and 1.44 years and accrued NHBs of 1.38, 0.86, and 0.57 QALYs, respectively. Thus, DMARD-failure patients on ADA+MTX incurred incremental NHBs of 0.51 (P < .05) versus IFX+MTX and 0.81 (P < .05) versus MTX alone. CONCLUSIONS: Understanding the benefit-risk tradeoff is important for clinicians when prescribing anti-TNFs. Both MTX-naïve and DMARD-failure patients may experience greater NHB when treated with ADA+MTX than when treated with IFX+MTX or MTX alone.