The economic, social, cultural and political milieus that influence injection drug-related HIV risk behaviors along the US–Mexico border in the previous decade have been studied comparing cities on an East–West axis. In an effort to inform interventions targeting factors beyond the individual level, we used a cross-sectional study design comparing people who inject drugs during 2016–2018, living on a North–South axis, in two cities—Ciudad Juárez, Chihuahua, Mexico and El Paso, Texas, USA—situated at the midpoint of the 2000 US–Mexico borderland stretch. We conceptualize injection drug use and its antecedents and consequences as influenced by factors operating at various levels of influence. Results of analysis comparing samples recruited from each border city indicated significant differences in demographic, socioeconomic, micro- and macro-level factors that affect risk. Similarities emerged in individual-level risk behaviors and some dynamics of risk at the drug use site most frequented to use drugs. In addition, analyses testing associations across samples indicated that different contextual factors such as characteristics of the drug use sites influenced syringe sharing. In this article, we reflect on the potential tailored interventions needed to target the context of HIV transmission risk among people who use drugs and reside in binational environment.