ABSTRACT: Substance use is prevalent among emergency department (ED) patients, and sex has been implicated as an important factor in the etiology, pathophysiology, sequelae, and treatment of substance use disorders. However, additional information is needed about the epidemiology of substance use as it relates to sex among ED patients.This study examined sex differences in the prevalence and severity of self-reported tobacco, alcohol, and drug use among adult ED patients.A random sample of English- or Spanish-speaking, non-critically ill or injured, 18- to 64-year-old patients was approached at two urban EDs and asked to self-report their lifetime and past 3-month tobacco, alcohol, and drug use. Participants completed the Alcohol, Smoking and Substance Involvement Screening Test (ASSIST) using an audio computer-assisted self-interview. Participants were categorized by their substance severity (ASSIST score) and need for a brief or more intensive intervention per World Health Organization recommendations. Substance misuse prevalence, frequency, severity, and need for interventions were compared between sexes by substance category. Multivariable logistic regression models were used to examine the association between sexes and the need for intervention after adjusting for sociodemographic characteristics.Of the 6,432 participants in the study, the median age was 37 years (interquartile range = 26 to 48 years), and 56.6% were female. Overall, lifetime, and past 3-month use was higher for men across all substances (tobacco, alcohol, and drugs). Among those reporting past 3-month use, the frequency of use was similar between sexes for tobacco and all drugs, but men reported more frequent alcohol use. Men had higher mean ASSIST scores compared to women, 30.3 (standard error [SE] ± 0.8) vs. 21.1 (SE ± 0.5); mean difference 9.2 (95% confidence interval [CI] = 7.4 to 10.9). The need for any intervention (brief or intensive) was similar between sexes for tobacco and drugs. After sociodemographic factors were adjusted for, women were less likely than men to need any intervention for alcohol (odds ratio [OR] = 0.6; 95% CI = 0.4 to 0.8), but not other substances: tobacco (OR = 0.9; 95% CI = 0.6 to 1.3), marijuana (OR = 0.8; 95% CI = 0.6 to 1.1), or other drugs (OR = 1.1; 95% CI = 0.7 to 1.7).Although men have a higher overall prevalence of substance use, the frequency and severity of use were similar for men and women for most substances. After other characteristics were adjusted for, sex appears associated with the need for interventions for alcohol, but not tobacco, marijuana, or other drugs.