Abstract Objectives: To examine the association between Colorado's legalization of recreational cannabis use and opioid-related deaths. Methods: We used an interrupted time-series design (2000-2015) to compare changes in level and slope of monthly opioid-related deaths before and after Colorado stores began selling recreational cannabis. We also describe the percent change in opioid-related deaths by comparing the unadjusted model-smoothed number of deaths at the end of follow-up with the number of deaths just prior to legalization. Results: Colorado's legalization of recreational cannabis sales and use resulted in a 0.7 deaths per month (b = -0.68; 95% confidence interval = -1.34, -0.03) reduction in opioid-related deaths....