The economic, social, cultural, and political milieus that influence HIV risk behaviors along the US-Mexico border are understudied. In an effort to appropriately inform interventions targeting structural influences, we compared injecting drug using populations living in two cities--Ciudad Juárez, Chihuahua and Tijuana, Baja California--situated on the Mexico-US border. These populations presented with similar demographic profiles, but differed significantly in terms of social and environmental influences that can influence both risk and protective factors (e.g., family drug use, migration, drug use patterns). We observed distinct behavioral and structural influences in these two border cities that will require tailored intervention strategies to reduce HIV transmission.