Objective. To assess the influence of biologic treatment patterns on healthcare costs for patients with rheumatoid arthritis (RA) initiating tumor necrosis factor-alpha (TNF-alpha) antagonist therapy. Methods. Patients with 2 RA diagnoses (International Classification of Diseases, 9th ed, 714.xx), and without psoriasis or Crohn's disease, were identified in a US employer-based insurance claims database. A sample of 2545 was constructed based on an index event of initiating TNF-alpha antagonist therapy and 30 months of continuous enrollment. Baseline characteristics were assessed in the 6-month pre-index period and treatment patterns were determined during the 12-month post-index period. Medical service and prescription drug costs were analyzed for Months 13-24 using multivariate regression analysis to control for baseline characteristics and time-varying confounding associated with treatment and disease severity. Results. In the first year after TNF-alpha initiation, 89% used a single TNF-alpha antagonist; only 9% and ;2% had switched TNF-alpha antagonists or received non-TNF biologic disease-modifying antirheumatic drugs, respectively. Descriptive analyses revealed pairwise differences between groups (p < 0.05) in baseline characteristics (comorbidities, RA-related procedure use, and prescription drug use). Controlling for observed baseline characteristics, costs were greater for those treated with multiple vs single TNF-alpha antagonists: annual RA-related prescription drug costs ($8,340 vs $7,058; p = 0.012), RA-related healthcare costs ($15,048 vs $13,312; p = 0.008), and total healthcare costs ($26,697 vs $21,381; p < 0.001). Conclusion. In this sample, the majority of patients with RA were treated with a single TNF-alpha antagonist over the first year on therapy. For those who switched therapy, Year 2 RA-related and total direct healthcare costs were higher, adjusting for claims-based measures of RA disease severity. (First Release Aug 15 2011; J Rheumatol 2011;38:2141-9; doi:10.3899/jrheum.101195)