OBJECTIVES: Opioid poisoning has increased substantially over the past decade, and has been associated with increases in opioid prescribing.  This has been accompanied by intervention efforts aimed at preventing and reversing opioid poisoning through naloxone prescription programs.  Understanding the economic burden of opioid poisoning can help inform these efforts and highlight the need for further interventions to attenuate current trends.  The main objectives of this study were to quantify the economic burden of opioid poisoning, estimate the cost per poisoning event, and to quantify costs of opioid poisoning for specific prescription opioids in the United States. METHODS: A cost-of-illness approach was used.  Direct costs related to hospitalization and ED visits and estimates for mortality and prevalence were obtained from nationally representative databases.  Other sources of direct costs were obtained from the literature.  Indirect costs included absenteeism and premature mortality costs, and were measured using the human capital method. One-way and probabilistic sensitivity analyses were used to test assumptions. RESULTS: Opioid poisoning resulted in an economic burden of approximately $20.4 billion in 2009.  Eighty-nine percent was attributed to productivity losses, of which 98% was from premature mortality.  Approximately $2.2 billion were attributed to direct medical costs.  Costs for heroin and prescription opioid poisoning were estimated to be $4.6 billion and $15.9 billion, respectively.  The cost per poisoning event was estimated to be $37,274 for all opioids.  The cost per poisoning event for heroin and prescription opioids was $33,793 and $38,541, respectively.  The three prescription opioids with the greatest poisoning costs were hydrocodone, oxycodone, and methadone. CONCLUSIONS: Opioid poisoning results in a significant economic burden to society.  Costs related to mortality account for the majority of the costs.  Interventions that prevent or reverse opioid poisoning can have significant impacts on cost, especially where death is prevented.