Background: The frequency of lethal overdose due to prescription and non-prescription drugs is increasing in North America. The aim of this study was to estimate overall and regional variation in incidence and outcomes of out-of-hospital cardiac arrest due to overdose across North America. Methods: We conducted a retrospective cohort study using case data for the period 2006-2010 from the Resuscitation Outcomes Consortium, a clinical research network with 10 regional clinical centers in United States and Canada. Cases of out-of-hospital cardiac arrest due to drug overdose were identified through review of data derived from prehospital clinical records. We calculated incidence of out-of-hospital cardiac arrest due to overdose per 100,000 person-years and proportion of the same among all out-of-hospital cardiac arrests. We analyzed the association between overdose cardiac arrest etiology and resuscitation outcomes. Results: Included were 56,272 cases, of which 1351 were due to overdose. Regional incidence of out-of-hospital cardiac arrest due to overdose varied between 0.5 and 2.7 per 100,000 person years (p < 0.001), and proportion of the same among all treated out-of-hospital cardiac arrests ranged from 0.8% to 4.0%. Overdose cases were younger, less likely to be witnessed, and less likely to present with a shockable rhythm. Compared to non-overdose, overdose was directly associated with return of spontaneous circulation (OR: 1.55; 95% CI: 1.35-1.78) and survival (OR: 2.14; 95% CI: 1.72-2.65). Conclusions: Overdose made up 2.4% of all out-of-hospital cardiac arrest, although incidence varied up to 5-fold across regions. Overdose cases were more likely to survive than non-overdose cases.