BACKGROUND: Long-term opioid therapy for chronic noncancer pain is becoming increasingly common in community practice. Concomitant with this change in practice, rates of fatal opioid overdose have increased. The extent to which overdose risks are elevated among patients receiving medically prescribed long-term opioid therapy is unknown. OBJECTIVE: To estimate rates of opioid overdose and their association with an average prescribed daily opioid dose among patients receiving medically prescribed, long-term opioid therapy. DESIGN: Cox proportional hazards models were used to estimate overdose risk as a function of average daily opioid dose (morphine equivalents) received at the time of overdose. SETTING: HMO. PATIENTS: 9940 persons who received 3 or more opioid prescriptions within 90 days for chronic noncancer pain between 1997 and 2005. MEASUREMENTS: Average daily opioid dose over the previous 90 days from automated pharmacy data. Primary outcomes–nonfatal and fatal overdoses–were identified through diagnostic codes from inpatient and outpatient care and death certificates and were confirmed by medical record review. RESULTS: 51 opioid-related overdoses were identified, including 6 deaths. Compared with patients receiving 1 to 20 mg/d of opioids (0.2% annual overdose rate), patients receiving 50 to 99 mg/d had a 3.7-fold increase in overdose risk (95% CI, 1.5 to 9.5) and a 0.7% annual overdose rate. Patients receiving 100 mg/d or more had an 8.9-fold increase in overdose risk (CI, 4.0 to 19.7) and a 1.8% annual overdose rate. LIMITATIONS: Increased overdose risk among patients receiving higher dose regimens may be due to confounding by patient differences and by use of opioids in ways not intended by prescribing physicians. The small number of overdoses in the study cohort is also a limitation. CONCLUSION: Patients receiving higher doses of prescribed opioids are at increased risk for overdose, which underscores the need for close supervision of these patients. PRIMARY FUNDING SOURCE: National Institute of Drug Abuse.