BACKGROUND Published data on the safety of tetanus-diphtheria-acellular pertussis vaccine (Tdap) in persons aged ≥65 years are limited. This study aims to examine a large cohort of Tdap users ≥65 years for evidence of increased risk of adverse events following vaccination. METHODS A matched cohort study design and a self-controlled case series (SCCS) design were used. The study population was adults aged ≥65 years who received the Tdap or tetanus and diphtheria (Td) vaccine during 1 January 2006-31 December 2010 at 7 health maintenance organizations in the United States. Seven major groups of prespecified events were identified electronically by diagnostic codes. RESULTS The study included 119 573 Tdap vaccinees and the same number of Td vaccinees. The results indicated that the risk of the prespecified events following Tdap was comparable to that following Td vaccination in this elderly population. There was a small increased rate of codes suggesting medically attended inflammatory or allergic events in 1-6 days following Tdap in the SCCS analysis (incidence rate ratio, 1.59 [95% confidence interval, 1.40-1.81]). CONCLUSION Although there is a small increased risk of medically attended inflammatory or allergic events in 1-6 days following Tdap compared to other time periods, it is no more common than that following Td. This study provides empirical safety data suggesting that immunizing adults aged ≥65 years with Tdap to reduce the risk of pertussis in the elderly and their contacts should not have untoward safety consequences.