The timing and regional specificity of cerebrospinal fluid (CSF) enlargements have not been well described in schizophrenia. High-resolution magnetic resonance images and computational image analysis methods were used to localize cross-sectional changes in lateral ventricle and sulcal and subarachnoid CSF in first episode schizophrenia patients (51 males/21 females) and healthy subjects (37 males/41 females). Volumes were obtained for each lateral ventricle horn and regional differences identified by comparing the distances from the ventricular surfaces to the central core at anatomically matched locations. Extra-cortical CSF differences were compared by measuring the proportion of CSF voxels sampled from spatially homologous cortical surface points. Significant extra-cortical CSF enlargements were observed in first episode patients, where regional differences surrounded the temporal, anterior frontal and parietal cortices. Volume and ventricular surface analyses failed to show significant effects of diagnosis. However, interactions indicated dorsal superior horn expansions in female patients compared with same-sex controls. Since ventricular enlargements are widely reported in chronic patients, our observations at first episode suggest ventricular enlargement may progress after disease onset with early changes occurring around the dorsal superior horn. In contrast, sulcal and subarachnoid CSF increases may be manifest near or before the first episode but after brain development is complete, reflecting pronounced reductions in proximal brain tissue.