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The impact of the changes in the gender composition of friendship networks during early adolescence on substance use in late adolescence was examined. The hypothesis was that initial level and increase in the proportion of other-sex friends in the network would be associated with higher levels of substance use among girls, but not among boys. Girls and boys (n=390) were interviewed annually from ages 12 to 18 (79% retention). For both boys and girls, initial level in the proportion of other-sex friends predicted alcohol use in late adolescence, whereas it was predictive of drug use in girls only. Moreover, for girls only, a faster increase in the proportion of other-sex friends in the network predicted later use of alcohol and drugs.