OBJECTIVES: The US Food and Drug Administration (FDA) requires drug manufacturers to implement Risk Evaluation and Mitigation Strategies (REMS) to ensure drug benefits outweigh their risks.  REMS for opioids target abuse, misuse, addiction, and overdose deaths.  This study aims to identify which among these REMS-designated risk categories contribute most to societal burden, where burden is the product of prevalence (or rate for death) and per-event cost.  This study also examines opioid diversion risk as a non-REMS secondary outcome. METHODS: Based on systematic review and meta-analysis, we estimated opioid-related mortality and prevalence for other outcomes.  For outcomes other than death, we estimated health care costs per occurrence as documented by the Healthcare Cost and Utilization Project (HCUP) dataset.  We focused on the value people place on avoiding death, rather than on the health care resources consumed.  As such, we estimated the cost of each death using the Environmental Protection Agency’s value of a statistical life (VSL), which reflects willingness to pay to avoid mortality risks. RESULTS: Excluding populations at high-risk for adverse behaviors, prevalence rates were 6% to 38% for misuse, 6% to 15% for abuse, 0.3% to 0.4% for addiction, and 9% to 20% for diversion.  Mortality varied widely, ranging from 1 to 108 per 100,000 person years.  Treatment costs per occurrence were $8,300 for abuse, $7,400 for addiction, and $10,000 for diversion.  Misuse had no documented treatment costs.  EPA’s VSL is $7.9 million.   CONCLUSIONS: Based on prevalence and per occurrence health care costs, abuse and diversion pose the greatest societal burden, but these findings require verification due in part to design differences across studies and differences among populations investigated.