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Objectives. To identify psychosocial risk factors for substance abuse among Mexican students and to offer elements for the design of prevention programs. Methods. A cross-sectional, nonexperimental study of a sample of 516 high school students in six of Mexico's most important cities. From April-June 2005, a customized version of the Drug Use Screening Inventory (revised) (DUSI-R) was administered. The analysis comprised eight factors: alcohol and drug abuse, affective disorders, poor self-control, poor school adjustment, low social competence, dysfunctional family relationships, social isolation, and being part of a detrimental social network (whose members take drugs and have antisocial attitudes). Factors predictive for illicit drug use were found by logistical regression, and a structural equation model was designed to determine the relationships among the factors. Results. The factors that predicted substance abuse were poor self-control with a tendency to act impulsively and aggressively; associating with troublemakers; and being frequently exposed to family conflicts, violence, and drug and/or alcohol use in the home. The structural equation model indicated that substance abuse is one of a group of disorders directly determined by associating with detrimental peers, and a higher rate of socioaffective disorders, and indirectly, by dysfunctional family relationships. Conclusions. Some of the suggestions made by theoretical models to explain substance abuse were confirmed. These empirically-supported elements can contribute to the design of prevention programs, especially those that are selective and recommended. [ABSTRACT FROM AUTHOR]