To examine the involvement of transforming growth factor-beta (TGF-beta) in the pathogenesis of prion diseases, immunohistochemical studies on both TGF-beta isoforms (beta 1, beta 2 and beta 3) and TGF-beta receptor type II (TGF-beta RII) were performed on the cerebral neocortices of 20 cases with human prion diseases, three cases with Alzheimer's disease, and five control cases. TGF-beta 2 immunoreactivity was thus detected in most neurons and astrocytes in all observed cases of prion disease. TGF-beta 3 immunoreactivity in the astrocytes and TGF-beta RII in the neurons were also detected in 17 of 20 cases with prion diseases. These immunoreactivities had increased markedly regarding the intensity and the number of positive cells in comparison to the control cases, but they were indistinguishable from those observed in Alzheimer's disease cases. In contrast, the TGF-beta 1 immunostaining did not show any apparent difference. Among the cases with prion diseases, however, no significant correlation was revealed between the immunohistochemical results and the clinical and pathological features. The results showed that TGF-beta isoforms thus appear to be differentially involved in the pathogenesis of prion diseases in a similar manner to that of Alzheimer's disease. Furthermore, two cases of prion disease in which pathological findings were free from astrogliosis and neuronal cell degeneration in the cerebral cortices also showed an increased immunoreactivity for TGF-beta 2. Thus, this result suggests that TGF-beta 2 may be involved in the early stages of neuronal cell degeneration in prion diseases.