Studies are needed that examine neurobiological characteristics in high-risk individuals prior to substance use disorder (SUD) development. In this pilot study, 4 adolescent subjects at high risk for SUD (having at least 1 parent with an SUD) were compared with 4 adolescent reference subjects on a cortico-limbic reactivity paradigm, where they were presented with affect-laden faces or geometric shapes. Functional magnetic resonance imaging was used to measure cortical activation in response to these stimuli. High-risk subjects, compared to low-risk, exhibited greater left amygdala activation ("t" = 2.76, "df" = 6, "p" = 0.03), suggesting they may exhibit hyperresponsivity of the amygdala in response to emotional stimuli.