Objectives: OxyContin was reformulated with a polyethylene oxide matrix in August 2010 to reduce the potential for intravenous abuse and for abuse by insufflation. The objective of this study was to evaluate the impact of OxyContin's reformulation on overdose (OD) risk for individuals dispensed OxyContin in comparison to those dispensed other opioids under regular care., Materials and Methods: Three national insurance databases with National Death Index linkage identified OD in individuals with any dispensing of OxyContin or a primary comparator opioid (extended release morphine, transdermal fentanyl, or methadone) between July 2008 through September 2015. A difference-in-differences design was used to compare the pre-post reformulation changes in OD rates for OxyContin versus comparators., Results: A total of 297,836 individuals were dispensed OxyContin and 659,673 individuals were dispensed a primary comparator across the 3 databases. Overall, there was little or no difference in the temporal change in OD incidence in comparators versus OxyContin (Medicaid: adjusted ratio-of-rate-ratios (aRoRs) ranging from 0.90 to 1.05; MarketScan/HIRD: aRoR ranging from 1.10 to 1.22). However, restriction to person-time without concomitant opioid use revealed a modestly greater reduction in OD incidence over time during OxyContin use, as the aRoRs comparing the primary comparators to OxyContin ranged from 1.06 to 1.30 in Medicaid and from 1.64 to 1.85 in MarketScan/HIRD., Discussion: This study did not detect an overall effect of the OxyContin reformulation on OD in insured patients under regular medical care. There is a suggestion of a modestly reduced OxyContin-associated OD risk following the reformulation but only in commercially insured individuals receiving single-opioid regimens., Competing Interests: This work was supported by Purdue Pharma L.P., Stamford, CT; HealthCore Inc., Wilmington, DE, STATinMED Research, Plano, TX, IBM Watson Health, Cambridge, MA, and World Health Information Science Consultants (WHISCON), Boston, MA received funding from Purdue Pharma L.P. to conduct this study and for the development of this manuscript. This underlying study was an FDA-mandated Post Market Requirement (PMR) study presented at the “Joint Meeting of the Drug Safety and Risk Management Advisory Committee (DSaRM) and the Anesthetic and Analgesic Drug Products Advisory Committee (AADPAC)” on September 10 to 11 2020. D.C.B. and K.H. are employees of HealthCore Inc. R.G., G.B., and L.L. were employees of HealthCore Inc. at the time of the study. L.B. is an employee of IBM Watson Health. H.Y. is an employee of New York City College of Technology-CUNY, Brooklyn, NY and collaborated as an external consultant to STATinMED Research for this study. A.M.W. is an employee of WHISCON. Purdue Pharma L.P. provided funding to HealthCore Inc., STATinMED Research, IBM Watson Health, and WHISCON to conduct this study and for the development of this manuscript. H.Y. declares no conflict of interest., (Copyright © 2022 The Author(s). Published by Wolters Kluwer Health, Inc.)