Tau-immunoreactive astrocytes in progressive supranuclear palsy (PSP) have a distinctive morphology and are referred to as tufted astrocytes (TA). We hypothesized that TA may be a degenerative change in reactive astrocytes. To test this hypothesis we examined the relationship of TA to gliosis in PSP. We first examined the distribution of gliosis [glial fibrillary acid protein (GFAP)-positive astrocytes], TA, neurofibrillary tangles (NFT) and pretangles in brain sections of neuropathologically pure PSP cases. Second, we examined PSP cases complicated by infarcts or Alzheimer's disease, since these cases would have reactive astrocytes associated with lesions. We used double immunostaining for GFAP and tau for cases with vascular lesions, and triple immunostaining for GFAP, tau and beta-amyloid protein for sections with senile plaques. There was no correlation between the distribution of gliosis and TA, with gliosis prominent in globus pallidus and subthalamic nucleus, and TA prominent in motor cortex and striatum. On the other hand, gliosis paralleled the distribution of NFT, but not the distribution of pretangles, suggesting that NFT contributes to gliosis in PSP. Although reactive astrocytes were present around infarcts and senile plaques, TA were not associated with these lesions. Tau accumulation in astrocytes in PSP was not preferential to (and was actually independent of) reactive astrocytes. This is consistent with the notion that tau accumulation in astrocytes is a degenerative rather than reactive process. Unlike NFT, astrocytic degeneration does not seem to contribute to gliosis or neuronal loss in PSP, and its clinical significance remains unclear.