Although the economic costs of substance misuse have been extensively examined in the published literature, information on the costs of nonmedical use of prescription opioids is much more limited, despite being a significant and rapidly growing problem in the United States. We estimated the current economic burden of nonmedical use of prescription opioids in the United States in terms of direct substance abuse treatment, medical complications, productivity loss, and criminal justice. We distributed our broad cost estimates among the various drugs of misuse, including prescription opioids, down to the individual drug level. In 2006, the estimated total cost in the United States of nonmedical use of prescription opioids was $53.4 billion, of which $42 billion (79%) was attributable to lost productivity, $8.2 billion (15%) to criminal justice costs, $2.2 billion (4%) to drug abuse treatment, and $944 million to medical complications (2%). Five drugs--OxyContin, oxycodone, hydrocodone, propoxyphene, and methadone--accounted for two-thirds of the total economic burden. The economic cost of nonmedical use of prescription opioids in the United States totals more than $50 billion annually; lost productivity and crime account for the vast majority (94%) of these costs.