Objectives. New onset heart failure (HF) has been associated with the use of TNF-α antagonists etanercept and infliximab based upon spontaneous adverse event reports. HF clinical trials of these agents were stopped early due to futility or worsening of existing HF. A potential association between etanercept and infliximab and new onset HF has been studied minimally at a population level. Methods. Using administrative claims from a large U.S. health care organization, we identified rheumatoid arthritis (RA) and Crohn's disease (CD) patients receiving infliximab or etanercept (exposed), and comparator cohorts of RA and CD patients receiving non-biologic immunosuppressives (unexposed). We studied adults < 50 years to reduce potential confounding related to common age-related comorbidities. Based on abstracted medical records of suspected HF cases, a physician panel adjudicated cases as definite, possible or no HF. Results. Among 4018 RA and CD patients with mean duration follow-upof 18 months, 9 of 33 suspected HF cases (identified using claims data) were adjudicated as definite (n = 5) or possible (n = 4) HF. The relative risk of HF among TNF-α antagonist-treated RA and CD patients was 4.3 and 1.2, respectively (P = NS for both). The absolute difference in cumulative incidence of HF among infliximab or etanercept-exposed compared to unexposed patients was 3.4 and 0.3 cases per 1000 persons for RA and CD (P = NS), respectively, yielding a number needed to harm of 294 for RA and 3333 for CD. Conclusion. We found only a small number of presumed HF cases (n = 9, or 0.2%) in a large population of relatively young RA and CD patients. Although there was an increased relative risk of incident, HF that was not statistically significant among those exposed to TNF-α antagonists compared to those unexposed, larger cohorts are needed to provide more precise risk estimates and permit adjustment for potential confounding. © Published by Oxford University 2007.