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Background: Illicit substance users may rely on mind-altering substances to regulate affect, especially when mental health symptoms are present., Objectives: In light of the prevalence of illicit substance use and symptoms of depression and anxiety among college students, as well as the affect regulation properties of illicit substances, we sought to examine whether differences in emotion dysregulation, depression, anxiety, and stress exist between illicit substance users and non-users., Methods: At a large Southwestern U.S. university, we examined differences in emotion dysregulation, depression, anxiety, and stress among college students who used illicit substances in the past 30 days (n = 92, 34.5%) and those who did not (n = 175, 65.5%). Data were collected in 2016 using two measures: the Difficulties in Emotion Regulation Scale (DERS; Gratz & Roemer, 2004) and the Depression Anxiety Stress Scales (DASS21; Lovibond & Lovibond, 1995)., Results: Results from the Descriptive Discriminate Analysis (DDA) indicated that significant differences existed between the two groups. Anxiety, difficulty clarifying emotions, difficulty employing goal-directed behaviors, and stress accounted the most for the group differences. Conclusion/Importance: Mental health differences between illicit substance users and nonusers exist. Specifically, illicit substance users reported more anxiety, stress, and difficulties with emotion regulation.