OBJECTIVES:  To estimate the risk of, and characterize risk factors associated with, serious opioid-induced respiratory depression (OIRD) among medical users of prescription opioids in two diverse patient populations and to evaluate the impact of providing automated, personalized, risk-mitigating clinical decision support on patient health outcomes and costs. METHODS:  This retrospective characterization of risk for serious prescription OIRD in national Veterans Health Affairs (VHA) and commercially insured populations (CIP) involved administrative claims data from 1.9 million VHA and over 18 million CIP patients who were dispensed a prescription opioid. Baseline factors associated with an event of serious OIRD among 7,234 cases and 28,932 controls in CIP were identified using multivariable logistic regression. RESULTS:  The strongest associations with serious OIRD in CIP were diagnosed substance use disorder (OR=10.20, 95% CI 9.06-11.40) and depression (OR=3.12, 95% CI, 2.84-3.42). Other strongly associated factors included other mental health disorders; impaired liver, renal, and pulmonary function; prescribed fentanyl, methadone and morphine; higher daily opioid doses; and concurrent psychoactive medications. The majority of risk factors were concordant in both populations, despite CIP being substantially younger; including more females and less chronic disease; and having greater prescribing prevalence of higher daily opioid doses. A statistically significant, monotonically increasing relationship between risk and adjusted average total monthly health care costs was observed in VHA ($1,226 versus $2,081, P=0.010, for lowest- and highest-risk patients, respectively). CONCLUSIONS: Risk for serious prescription OIRD among subgroups of patients with private or public health insurance is high, despite differences in demographics, clinical conditions, health care delivery systems, and clinical practices. The identification of patients at high risk for overdose through automated characterization of risk factor profiles and provision of personalized risk-mitigating measures has substantial potential to reduce the morbidity, mortality, and health care costs due to serious prescription OIRD.