OBJECTIVES: Estimate the costs of prescription opioid analgesic (“RxO”) abuse in the U.S., and costs savings realized from introducing abuse-deterrent formulations (“ADFs”). METHODS: The costs associated with RxO abuse were grouped into three major cost categories: health care, lost productivity, and criminal justice. Each category has multiple underlying components. Relying primarily on published data, we used varying methods depending on the cost component considered. In general, cost estimates and potential cost savings due to specific characteristics of ADFs were obtained by either: a) multiplying the relevant number of RxO abusers based on various national surveys (e.g., National Household Survey on Drug Abuse, Treatment Admissions Data Set, Drug Abuse Warning Network) for prevalence estimates by the per abuser cost; or b) determining the overall costs to the U.S. for drug abuse in general and apportioning the share due to RxO abuse. RESULTS: Total costs of RxO abuse in the U.S. in 2006 USD were approximately $10 billion. Of these costs, $3 billion were health care costs, $5.2 billion were lost productivity costs, and $1.8 billion were criminal justice costs. These estimates are conservative in that some cost categories and components are not included. Sensitivity analyses found that costs for the estimated cost categories and components could range higher. CONCLUSION: The costs of RxO abuse in the U.S. impose a substantial economic burden to society. Rising trends of RxO abuse internationally suggest an escalating economic and public health burden in coming years, and the development and introduction of ADFs could save much money.