Progressive supranuclear palsy (PSP) and Parkinson's disease (PD) are neurodegenerative diseases with distinctive pathological appearances. Early clinical diagnosis can be difficult. MRI may help differentiate PSP from PD, but the differences are often only obvious with advanced disease. It would be useful to have an unbiased assessment of difference to guide visual assessment of MRI as an aid to clinical diagnosis. Voxel-based morphometry (VBM) offers nonbiased, observer-independent morphometric MRI analysis. Our objectives were to assess structural differences between PSP, PD, and normal controls and test the clinical utility of the results. T1-weighted MR images in 12 patients with clinically diagnosed PSP, 12 with PD, and 12 age- and sex-matched controls were normalized to a common stereotaxic space and segmented into gray matter (GM) and white matter (WM) then analyzed using VBM. MRI scans were reviewed by a neuroradiologist blinded to the clinical diagnosis and assigned to the "non-PSP" or "PSP" group based on regional differences highlighted using VBM. VBM revealed significant group differences between PSP and PD as well as PSP and controls, with tissue reduction demonstrated in the region of the cerebral peduncles and midbrain. With these regional differences as a guide, neuroradiological diagnosis achieved a sensitivity of 83% and a specificity of 79%. VBM did not detect dramatic changes in frontal regions despite significant frontal cognitive decline in the PSP group. Pathology in the basal ganglia rather than tissue loss in the frontal lobes could be responsible for this. This information may help in the differentiation of PSP in clinical practice.