Objective. Limited evidence exists comparing the persistence, effectiveness, and costs of biologic therapies for rheumatoid arthritis in clinical practice. Comparative effectiveness studies are needed to understand real-world experience with these agents. We evaluated treatment patterns, costs, and effectiveness of tumor necrosis factor inhibitor (TNFi) agents in patients enrolled in the Veterans Affairs Rheumatoid Arthritis (VARA) registry. Methods. Observational data from the VARA registry and linked administrative databases were analyzed. Longitudinal data from VARA patients initiating adalimumab (ADA), etanercept (ETN), or infliximab (IFX) from 2003 (the date all agents were available within the Veteran Affairs) to 2010 were analyzed. Outcomes included Disease Activity Score using 28 joints (DAS28), treatment persistence, dose escalation, and direct costs of drugs and drug administration. Results. For 563 eligible patients, baseline DAS28, DAS28 improvements, and persistence on initial treatment were similar across agents. Fewer patients receiving ETN (n = 5/290; 2%) underwent dose escalation than did patients taking ADA (n = 32/204; 16%) or IFX (n = 44/69; 64%). Annual costs for first course of TNFi therapy were lower for injectable ADA ($13,100 US) and ETN ($13,500 US) than for intravenously administered IFX ($16,900 US). Conclusion. Despite similar persistence and clinical disease activity for these TNFi agents, rates of dose escalation were highest with ADA and IFX. Higher overall costs were noted for IFX without increases in effectiveness.