The objective of the study was to identify and evaluate factors that are associated with differences in substance abuse between non-acculturated and acculturated Hispanic youth. We employed t-test and logistic regression to analyze self-reported survey data from 8,200 self-described Hispanic students. The outcome variable was past 30-day use of marijuana and the key independent variable was language used at home (English/Spanish). The covariates were 32 psychosocial risk and protective factors for drug use. All the risk factor scores that were significantly different for the two groups had higher means, indicating greater risk, for English-speakers, while all the seven protective factors that were significantly different had higher mean scores, indicating greater protection, for the Spanish speakers. In multivariate analysis, the odds ratios for language used at home range from 1.60 (p less than 0.00) for the basic model to 1.05 (p = 0.62) for models that incorporated the psychosocial factors. Findings confirm literature reports suggesting that language used at home is a strong predictor of adolescent substance use. This effect may be mediated principally through the family and peer/individual psychosocial domains. (Contains 2 figures and 5 tables.)