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Cumulative risk is a parsimonious methodology that provides better model stability and more statistical power, yet it has only been recently used in substance use research. The aim of this study is to investigate multiple aspects of substance use risk in a population in need of substance use prevention and intervention services.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>We conducted a cross\u2010sectional study of community college students (<jats:italic>N<\/jats:italic>\u2009=\u2009288; 75% female) examining the relative contributions of different domains of cumulative risk (eg, life stressors, academic stressors, and mental health diagnoses) to develop different profiles of risk across substance use classes (ie, alcohol, cigarette, marijuana, and hard drug use).<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Cumulative risk analyses indicated that alcohol and tobacco use were associated with the domains of life stressors and peer\/family substance use, marijuana use with peer\/family substance use and stressful childhood experiences, and hard drug use with peer\/family substance use, lack of social support, low access to care, and stressful childhood experiences.<\/jats:p><\/jats:sec><jats:sec><jats:title>Discussion and Conclusions<\/jats:title><jats:p>Different strategies for prevention and intervention may be necessary to effectively address different forms of substance use in this population.<\/jats:p><\/jats:sec><jats:sec><jats:title>Scientific Significance<\/jats:title><jats:p>The risk domain profiles related to specific drugs may lead to targeted interventions to reduce substance use in community college students. 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