Fourteen factors related to drug use were selected from the data on Latino, Latina, and white teenagers and assigned empirically to either a multiple protective (PFI) or risk factor (RFI) index. Both bivariate and multiple regression analyses were used to examine the relationships of the RFI, PFI, and their interaction on frequency and/or quantity of cigarette, alcohol, cannabis, cocaine, and hard drug use. The PFI index and the RFI index and their interaction contributed significantly to frequency and quantity of drug use among all groups. As the RFI increased, protective factors were less effective buffers for frequency of hard drug use in white and Latino adolescents, for frequency of cocaine use among Latina adolescents, for frequency and quantity of alcohol use among white adolescents, for frequency of cocaine use among white adolescent males, and quantity of cigarettes used by white adolescent females. Study findings provide support for the conclusion that protective and risk factors for Latino adolescent drug use are partly related and partly distinct constructs. 5 tables and 58 references