Young adults might engage in many risk behaviors, including alcohol and drug use, which could lead to mental health problems, such as suicide. The aim of this study was to examine specific psychosocial and clinical factors that could influence the possible relationship between polysubstance use (PSU) and suicide risk in a sample of young Colombian participants.A sample of 274 young participants (mean age = 21.3 years) was evaluated with two substance use screening tests (ASSIST and AUDIT) and five scales for clinical and psychosocial factors and suicide risk: The Center for Epidemiologic Studies Depression scale, Zung Self-Rating Anxiety scale, Family APGAR, the Childhood Trauma Questionnaire, and the Plutchik Suicide Risk scale. Correlation and multiple regression analyses were conducted.Use of cannabis and tobacco was significantly correlated with suicide risk in the total sample (p < .05). Depressive and anxiety symptoms, family functioning, and emotional abuse during childhood were significantly associated with suicide risk (p < .001), while alcohol use, anxiety symptoms, and family functioning were variables significantly related to PSU.Our findings are consistent with previous evidence suggesting a relationship between substance use, several psychosocial factors, and suicide risk in young participants.Our study is one of the first reports the relationship between substance use and suicide risk in a Latin American population. (Am J Addict 2017;26:388-394).