Background <p>People who use drugs report hesitance to seek employment because of stigma around drug use, which other forms of stigma may compound. We evaluated risk factors for substance use-related employment stigma among emergency department (ED) patients who use drugs.</p> Methods <p>This was a cross-sectional study among ED patients at high risk of opioid overdose in Rhode Island. The outcomes were three self-reported measures of substance use-related employment stigma. Multivariable log-binomial regression was used to estimate the association between participant characteristics and each outcome.</p> Results <p>Among 648 participants, 25.8% reported they had been turned down for a job due to current/past drug use, 40.8% disagreed that most employers will hire someone treated for drug use if qualified, and 77.7% agreed that most employers will pass over applicants treated for drug use in favor of others. Females reported they had been turned down for a job due to drug use less often than males (adjusted prevalence ratio [PR] 0.72, 95% confidence interval [CI] 0.53–0.98). Persons with a history of homelessness (aPR 1.82, 95% CI 1.24–2.66) and addiction treatment (aPR 1.95, 95% CI  1.22–3.12) more often reported having ever been turned down for a job due to drug use. Race/ethnicity was not associated with substance use-related employment stigma.</p> Discussion <p>Perceived substance use-related employment stigma was common among ED patients who use drugs, and men and those with a history of homelessness or addiction treatment may be particularly affected. Employers can diminish the harms of stigmatization by acknowledging those who struggle with addiction and changing hiring practices to reduce stigma.</p>