© 2017 American Academy of Pain Medicine. Objective. To characterize the risk factors associated with overdose or serious opioid-induced respiratory depression (OIRD) among medical users of prescription opioids in a commercially insured population (CIP) and to compare risk factor profiles between the CIP and Veterans Health Administration (VHA) population. Subjects and Methods. Analysis of data from 18,365,497 patients in the IMS PharMetrics Plus health plan claims database (CIP) who were dispensed a prescription opioid in 2009 to 2013. Baseline factors associated with an event of serious OIRD among 7,234 cases and 28,932 controls were identified using multivariable logistic regression. The CIP risk factor profile was compared with that from a corresponding logistic regression among 817 VHA cases and 8,170 controls in 2010 to 2012. Results. The strongest associations with serious OIRD in CIP were diagnosed substance use disorder (odds ratio [OR] 5 10.20, 95% confidence interval [CI] 5 9.06-11.40) and depression (OR5 3.12, 95% CI52.84-3.42). Other strongly associated factors included other mental health disorders; impaired liver, renal, vascular, and pulmonary function; prescribed fentanyl, methadone, and morphine higher daily opioid doses; and concurrent psychoactive medications. These risk factors, except depression, vascular disease, and specific opioids, largely aligned with VHA despite CIP being substantially younger, including more females and less chronic disease, and having greater prescribing prevalence of higher daily opioid doses, specific opioids, and most selected nonopioids. Conclusions. Risk factor profiles for serious OIRD among US medical users of prescription opioids with private or public health insurance were largely concordant despite substantial differences between the populations in demographics, clinical conditions, health care delivery systems, and clinical practices.