OBJECTIVES: While the economic costs of substance abuse have been extensively examined in the published literature, information on the costs of abuse of prescription opioids is more limited, despite this rapidly growing problem in the US. The National Survey of Drug Use and Health (NSDUH) estimated that, between 2001 and 2006, the number of persons using prescription pain relievers for nonmedical purposes increased from 3.5 million to 5.2 million. We sought to estimate the economic burden of prescription opioid abuse in the US. METHODS: We estimated the current economic burden of prescription opioid abuse in the US in terms of direct substance abuse treatment, medical complications, productivity loss, and criminal justice. Utilizing information from NSDUH, we distributed our broad cost estimates among the various drugs of abuse, including prescription opioids, down to the individual drug level. Data sources included the National Expenditures for Mental Health Services and Substance Abuse Treatment; the CDC's mortality database and HIV/AIDS Surveillance Report; the Office of National Drug Control Policy's estimates of the economic costs of drug abuse in the US; the US DOJ's Uniform Crime Statistics, profiles of prison and jail inmates and expenditure and employment reports; and the published literature. RESULTS: The estimated 2006 total cost of prescription opioid abuse was $53.4 billion, of which $42 billion (79%) was attributable to productivity loss, $8.2 billion (15%) to criminal justice costs, $2.2 billion (4%) to abuse treatment, and $944 million to medical complications (2%). In our analysis of costs by specific prescription opioids, five drugs—OxyContin, oxycodone, hydrocodone, propoxyphene, and methadone—accounted for two thirds of all prescription-opioid-attributable costs. CONCLUSIONS: The great majority of the economic costs of opioid abuse, 94%, are accounted for by lost productivity and crime. The burden of prescription opioid abuse in the US is high and will likely continue to grow.