In this study we developed separate risk and protective factor indices to examine vulnerability to drug use among Latino high school students. Survey data were collected from 516 Latino 9th and 10th grade youth in the Los Angeles area. Frequency and quantity of use data were collected for cigarettes, alcohol, marijuana, inhalants, cocaine, and other illicit drugs. Few gender differences emerged in prevalence of drug use and about 25% were already involved in heavy drug use. Seventeen variables were examined for inclusion in a risk factor index (RFI) or protective factor index (PFI). Bivariate, multivariate, and structural equation models (SEM) were employed in the analysis of data. All of the variables except for one were more risk-inducing than protective for these Latino youth. However, as a group, the PFI predicted several types of drug use for boys and girls, and moderated the adverse effects of the RFI. At a high level of risk, a high level of protection was associated with reduced use for some types of drugs. In the SEM, vulnerability to drug use as indicated by the RFI and PFI was strongly associated with drug use for both boys and girls and more strongly related to drug use than the RFI or PFI alone. These results have exciting implications for intervention.