Glial cytoplasmic inclusions (GCIs) and microglia were quantified in 12 cases of multiple system atrophy (MSA) with special reference to their association with histologically defined lesion severity. The targets of the analysis were white matter (cerebellum, pontine base) and gray matter (putamen, substantia nigra). First, the lesion severity was defined: for white matter, the degree of demyelination and tissue rarefaction were semi‐quantified on Klüver‐Barrera (KB) sections as grade I (mildly injured), II (moderately injured), and III (severely injured); for gray matter, neurons and astrocytes were counted on KB and glial fibrillary acidic protein‐immunostained sections, respectively. Next, the GCI burden was quantified on sections immunostained for α‐synuclein, phosphorylated α‐synuclein, and ubiquitin and the microglial burden was quantified on sections immunostained for HLA‐DR. In white matter, the GCI and microglial burdens were the greatest when the tissue injury was mild and/or moderate (grade I and/or grade II), and they became less prominent when the tissue injury became more severe (grade III). In gray matter, in contrast, the GCI and microglial burdens failed to show significant correlations with the lesion severity. Our result suggests that the amount of GCIs as well as that of microglia is reduced when the tissue injury becomes severe in vulnerable white matter areas, but not in vulnerable gray matter areas, of MSA. It also suggests that there seems to be a difference between gray matter and white matter in the way GCIs and microglia participate in the degenerative process of MSA.