This article reports the results of a descriptive study conducted with middle school and high school age youth residing in northwestern Spain. The main outcome of the study is to advance knowledge about the drug use attitudes and behaviors of immigrants versus native youth in a social context where Latin American immigrants share a common language and a set of core cultural norms with the host society. The research was conducted by a bi-national Spain-US research team as a preliminary study leading to the development of joint culturally appropriate prevention interventions for youth in the northern region of Galicia, Spain. Surveys were administered in Spring 2005 to 817 students in 7th to 10th grades in 10 urban, secondary schools with high immigrant enrollment. The sample included Spanish natives (two-thirds) and Latin American immigrants (one-third), mainly from Colombia, Argentina, and Venezuela. Multiple regression analyses predicted substance use intentions, and a composite variable measuring lifetime and last 30-day frequency and amount of alcohol, cigarette and marijuana use. Controlling for the fact that the immigrant students were generally older and performing less well academically than natives, and for other predictors, Latin American immigrant youth were less at risk than native youth on their intentions to use substances and on their reported actual substance use. In a mediational analysis, most of the key explanatory variables in youth substance use etiology failed to account for the immigrant versus native differences, including a range of risk and protective factors for substance use, substance use norms, strength of ethnic identity, and degree of social integration within native-born social networks. Differential access to drugs mediated the immigrant-native gap in substance use intentions but did not mediate differences in actual substance use.