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Background Published structural neuroimaging studies of prenatal cocaine exposure (PCE) in humans have yielded somewhat inconsistent results, with several studies reporting no significant differences in brain structure between exposed subjects and controls. Here, we sought to clarify some of these discrepancies by applying methodologies that allow for the detection of subtle alterations in brain structure. Methods We applied surface-based anatomical modeling methods to magnetic resonance imaging (MRI) data to examine regional changes in the shape and volume of the caudate and putamen in adolescents with prenatal cocaine exposure (n = 40, including 28 exposed participants and 12 unexposed controls, age range 14 to 16 years). We also sought to determine whether changes in regional brain volumes in frontal and subcortical regions occurred in adolescents with PCE compared to control participants. Results The overall volumes of the caudate and putamen did not significantly differ between PCE participants and controls. However, we found significant (P Conclusions Prenatal cocaine exposure may lead to subtle and regionally specific patterns of regional dysmorphology in the striatum and volumetric changes in the frontal lobes. The localized and bidirectional nature of effects may explain in part the contradictions in the existing literature.