Cerebral cortical changes in 10 cases with Pick's disease were studied immunocytochemically and ultrastructurally. All cases contained Pick's argentophilic bodies and ballooned neurons. The antibodies against phosphorylated tau proteins that intensely stained all Pick bodies recognized numerous neuronal processes around Pick body–bearing cells and focal portions in the perikarya of ballooned neurons. Monoclonal and polyclonal anti-ubiquitin antibodies stained not only some Pick bodies with variable intensity, but also the perikarya of all ballooned neurons. Ultrastructurally, Pick bodies consisted of accumulation of randomly oriented, approximately 15-nm straight filaments and paired twisted profiles with a minimal diameter of 13 nm, maximal diameter of 26 nm, and twist periodicity of 120 nm. These Pick body–type filaments were also observed in the perikarya of ballooned neurons and neuronal processes around Pick body–bearing cells. Our studies demonstrate, for the first time, the characteristic pathological feature of neuropil in Pick's disease. Pick body–bearing cells and ballooned neurons show unique immunocytochemical and ultrastructural properties that may be a clue to the pathogenesis of Pick's disease.