Introduction: Substance and opioid misuse present significant illness burdens in Emergency Departments (EDs). Understanding risk factors for mortality in these patients is urgently needed to allow targeted prevention. This studys objective was to determine whether frequent ED use is independently associated with mortality among patients with substance and opioid misuse, and secondarily, whether degree of frequent use influences mortality risk. Methods: This is a retrospective cohort study in Alberta, Canada. National Ambulatory Care Reporting System ED data was linked to Vital Statistics mortality data using postal code, birthdate, and sex. All adults (18 years old at index visit, i.e. first visit made in the study year) with substance or opioid misuse (defined by ICD-10 codes) from April 1, 2012 to March 31, 2013 were included. Frequent use was defined by 5 ED visits in the 12 months prior to index visit. The primary outcome was mortality within 90 days, and secondarily, within 30 days, 365 days, and 2 years post-index visit. Mortality was compared using Kaplan-Meier curves and Cox regression adjusting for age, sex and income. Degree was examined by subcategorizing frequent use into 5-10, 11-15, 16-20, and >20 visits. Results: Overall, 16,389 patients made 24,880 visits for substance misuse, and 1787 patients made 2241 visits for opioid misuse. Frequent vs. non-frequent substance misusers were older, more often female, lower income, more often of rural residence, and arrived more by ambulance for lower acuity visits that were hospitalized less often. Compared to frequent substance misusers, frequent opioid misusers were more often female, of non-rural residence, arrived less often by ambulance, and made higher acuity visits that were hospitalized more often. Among substance misuse patients, 97.1% (95% CI: 96.6, 97.7) of frequent users vs. 98.0% (95% CI: 97.7, 98.2) of non-frequent users were alive at 2 years. Frequent use was significantly associated with mortality at 365 days (HR 1.36 [95% CI: 1.04, 1.77]) and 2 years (HR 1.32 [95% CI: 1.04, 1.67]) but not at 90 or 30 days. Subcategorized by degree, frequent use was significantly associated with mortality only for patients with >20 visits/year at 365 days (HR 1.88 [1.03, 3.44]) and 2 years (HR 1.89 [1.10, 3.22]). Among opioid misuse patients, there was no difference in mortality between frequent and non-frequent ED users at any time point. However, subcategorized by degree, a significant association was seen for those with 16-20 visits/year at 365 days (HR 3.62 [95% CI:1.13, 11.66]), and 2 years (HR 3.37 [95% CI: 1.05, 10.81]). Conclusion: In substance misuse patients, frequent ED use was significantly associated with long-term but not short-term mortality. Mortality risk for substance and opioid misuse patients was concentrated in extremely frequent users suggesting that the highest frequency presenters should be targeted for prevention.