We assess the effects of in utero cocaine and polysubstance exposure on the adolescent caudate nucleus through high-resolution magnetic resonance imaging. Cocaine exposure may compromise the developing brain through disruption of neural ontogeny in dopaminergic systems, effects secondary to fetal hypoxemia, or altered cerebrovascular reactivity. Cocaine exposure may also lead to neonatal lesions in the caudate. However, long-term or latent effects of intrauterine cocaine exposure are rarely found. We use T(1)-weighted magnetic resonance imaging to quantify caudate nucleus morphology in matched control and exposed groups. The literature suggests that in utero cocaine exposure consequences in adolescents may be subtle, or masked by other variables. Our comparison focuses on contrasting the control group with high-exposure subjects (mothers who reported 2 median of 117 days of cocaine use during pregnancy; 82% tested positive for cocaine use at term). We use advanced image registration and segmentation tools to quantify left and right caudate morphology. Our results indicate that the caudate is significantly larger in controls versus subjects (P < 0.0025), implying cocaine exposure-related detriments to the dopaminergic system. The right (P < 0.025) and left (P < 0.035) caudate, studied independently, show the same significant trend. Permutation testing and the false discovery rate were used to assess significance.