The aim of this study is to evaluate tumor necrosis factor (TNF) inhibitor persistence and the impact of comorbidity on treatment persistence in patients with rheumatoid arthritis (RA). In a Korean National Health Insurance claims database, patients with a diagnosis code of RA (M05 or M06) who started TNF inhibitor therapy between July 1, 2007 and June 30, 2008 were enrolled. The study cohort was followed until December 31, 2009. Persistence was examined using Kaplan-Meier survival analysis, and multivariate Cox proportional hazard models were developed to examine the potential impact of comorbidities on drug persistence. A total of 388 patients were enrolled in the study cohort. The mean persistence rate in the overall population was 61% at 18 months. Drug survival rates for adalimumab and etanercept at 6 months were 82 and 85%, respectively, and 73 and 78%, respectively, at 12 months. Charlson comorbidity index (CCI) scores and comorbidities such as diabetes, chronic pulmonary disease, mild liver disease, and depression at initiation were not related with drug persistence, while peptic ulcer disease (PUD) lowered the risk of discontinuation of TNF inhibitors (HR 0.73, 95% CI 0.55-0.97). Old age (HR 1.59, 95% CI 1.09-2.33) and prescription of inhibitors by an internist (HR 1.59, 95% CI 1.02-2.48) were associated with discontinuation of TNF inhibitors. The persistence of TNF inhibitors was 61% at 18 months. CCI score and other comorbidities were not related with early discontinuation of TNF inhibitors, while PUD was an independent contributing factor to TNF inhibitor persistence.