Background: More than half of enrollees in the U.S. Department of Veterans Affairs (VA) are also covered by Medicare and can choose to receive their prescriptions from VA or from Medicare-participating providers. Such dual-system care may lead to unsafe opioid use if providers in these 2 systems do not coordinate care or if prescription use is not tracked between systems. Objective: To evaluate the association between dual-system opioid prescribing and death from prescription opioid overdose. Design: Nested case–control study. Setting: VA and Medicare Part D. Participants: Case and control patients were identified from all veterans enrolled in both VA and Part D who filled at least 1 opioid prescription from either system. The 215 case patients who died of a prescription opioid overdose in 2012 or 2013 were matched (up to 1:4) with 833 living control patients on the basis of date of death (that is, index date), using age, sex, race/ ethnicity, disability, enrollment in Medicaid or low-income subsidies, managed care enrollment, region and rurality of residence, and a medication-based measure of comorbid conditions. Measurements: The exposure was the source of opioid prescriptions within 6 months of the index date, categorized as VA only, Part D only, or VA and Part D (that is, dual use). The outcome was unintentional or undetermined-intent death from prescription opioid overdose, identified from the National Death Index. The association between this outcome and source of opioid prescriptions was estimated using conditional logistic regression with adjustment for age, marital status, prescription drug monitoring programs, and use of other medications. Results: Among case patients, the mean age was 57.3 years (SD, 9.1), 194 (90%) were male, and 181 (84%) were non-Hispanic white. Overall, 60 case patients (28%) and 117 control patients (14%) received dual opioid prescriptions. Dual users had significantly higher odds of death from prescription opioid overdose than those who received opioids from VA only (odds ratio [OR], 3.53 [95% CI, 2.17 to 5.75]; P < 0.001) or Part D only (OR, 1.83 [CI, 1.20 to 2.77]; P = 0.005). Limitation: Data are from 2012 to 2013 and cannot capture prescriptions obtained outside the VA or Medicare Part D systems. Conclusion: Among veterans enrolled in VA and Part D, dual use of opioid prescriptions was independently associated with death from prescription opioid overdose. This risk factor for fatal overdose among veterans underscores the importance of care coordination across health care systems to improve opioid prescribing safety.