Aquaporin 4 (AQP4), one of the water channel proteins on the plasma membrane of astrocytes, is up-regulated in various conditions with brain edema. Possible participation of AQP4 in various inflammatory lesions, more or less associated with edema, was examined in human autopsied brains. Immunohistochemistry was used to investigate AQP4 expression in autopsied brains with multiple sclerosis (MS), human immunodeficiency virus encephalitis (HIVE) or progressive multifocal leukoencephalopathy (PML). The cellular localization of AQP4 and its relation to inflammatory lesions were then examined with double-labeling immunohistochemistry. AQP4 immunoreactivity (IR) was restricted to astrocytes and localized to their entire processes, including their endfeet facing the abluminal surface of capillaries. In MS brains, AQP4-positive astrocytes were more abundant at the periphery of plaques than in their center, as seen in ischemic foci. Quantification of fluorescent signal demonstrated that AQP4 IR was greatly increased around plaques relative to that in unaffected area. Although the white matter was severely involved in HIVE and PML, AQP4-positive astrocytes were rare in the white matter even around perivascular active inflammatory foci. They were abundant in the gray matter and most prominent in the boundary between the gray and white matter, without apparent relation to inflammatory foci. Some bizarre astrocytes in PML exhibited AQP4 IR. Up-regulation of AQP4 was consistently found in astrocytes in various inflammatory lesions. However, the distribution of AQP4-positve astrocytes differed markedly according to disease and was not necessarily related to brain edema, indicating that functions and regulation of AQP4 in human brains are multiple.