The use of chronic opioid therapy (COT) for chronic non-cancer pain (CNCP) has increased dramatically in the past two decades. There has also been a marked increase in the abuse of prescribed opioids and in accidental opioid overdose. Misuse of prescribed opioids may link these trends, but has thus far only been studied in small clinical samples. We therefore sought to validate an administrative indicator of opioid misuse among large samples of recipients of COT and determine the demographic, clinical, and pharmacological risks associated with possible and probable opioid misuse. A total of 21,685 enrollees in commercial insurance plans and 10,159 in Arkansas Medicaid who had at least 90 days of continuous opioid use 2000-2005 were studied for one year. Criteria were developed for possible and probable opioid misuse using administrative claims data concerning excess days supplied of short-acting and long-acting opioids, opioid prescribers and opioid pharmacies. We estimated possible misuse at 24% of COT recipients in the commercially insured sample and 20% in the Medicaid sample and probable misuse at 6% in commercially insured and at 3% in Medicaid. Among non-modifiable factors, younger age, back pain, multiple pain complaints and substance abuse disorders identify patients at high risk for misuse. Among modifiable factors, treatment with high daily dose opioids (especially >120 mg MED per day) and short-acting Schedule II opioids appears to increase the risk of misuse. The consistency of the findings across diverse patient populations and the varying levels of misuse suggest that these results will generalize broadly, but await confirmation in other studies.