Despite widespread efforts to curb opioid prescribing, opioid misuse remains a patient safety crisis. This observational study used mortality data from the Centers for Disease Control and Prevention to estimate opioid-related mortality among children between 1999 and 2016. During this period, opioid-related mortality increased significantly, with an overall rate of nearly 1 per 100,000. Opioid-related mortality was highest for adolescents ages 15 to 19 and was significantly higher for males compared with females. These results underscore the importance of addressing the opioid epidemic in order to improve pediatric patient safety. A previous PSNet interview discussed the opioid epidemic and strategies to address this growing patient safety concern.