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The paper presents a non-experimental and descriptive research, aimed to identify the use of legal and illegal psychoactive drugs and the psychosocial associated risk and protective factors in a sample of 763 college students from Cali, Colombia. A questionnaire to evaluate the use of 4 illegal drugs, 2 legal drugs and 13 psychosocial factors was designed and validated. It was found that the legal drug with a higher level of consume was alcohol and the illegal drug was marijuana. The results show a significant association of psychosocial risk and protective factors with the use of both legal drugs (alcohol c2 = 16,54, p = 0,000; tobacco c2 = 39,07, p = 0,000) and the use of all the illegal drugs (marijuana c2 = 28,41, p = 0,000; ecstasy c2 = 17,04, p = 0,000; opiates c2 = 6,77, p = 0,034; and cocaine c2 = 8,89, p = 0,012). The associated factors for all drugs are specifically: disruptive behaviors, self-control, beliefs and valuation of PAS and the relation with consumers.