Several neurodegenerative disorders contain tau-immunoreactive neuronal and glial inclusions throughout the cerebral cortex and brainstem. Although these diseases have been considered distinct clinicopathological entities, recent recognition of many neuropathological and clinical parallels has raised the question of overlap between the disorders. In addition, histopathological similarities sometimes complicate neuropathological diagnosis. To address these issues, we examined the morphology and differential distribution of pathologic lesions in three disorders: progressive supranuclear palsy, Pick's disease, and corticobasal degeneration. We found considerable similarity in the anatomical regions affected by the three entities; however, semiquantitative analysis revealed differential anatomical susceptibility. Similarly, although overlap existed in the morphology of tau-immunoreactive inclusions, characteristic differences remained and may be useful in differential diagnosis. In particular, glial inclusions varied dramatically between the disorders. Despite significant overlap among the three neurodegenerative diseases examined, the morphological and regional differences suggest that each is a distinct pathophysiological entity.