Cryptococcal meningoencephalitis (CME) is caused by the encapsulated fungus Cryptococcus neoformans (CN) and is a major cause of mortality and morbidity in patients with AIDS. The polysaccharide capsule of CN is important for virulence, and soluble polysaccharide has the potential to cause immune modulation. To better understand the interactions of central nervous system cells and cryptococcal capsular polysaccharide (CNPS) in the pathogenesis of human CME, postmortem brain tissue from 21 patients with CME (13 AIDS and 8 non-AIDS patients) was analyzed. Histopathology and distribution of tissue CNPS antigen were analyzed using monoclonal antibodies against CNPS in combination with cell type-specific markers (glial fibrillary acidic protein for astrocytes, Ricinus communis agglutinin (RCA)-l for macrophage/microglia and endothelial cells; UCHL-1 for T cells, L26 for B cells). The CN cells showed discrete capsular immunoreactivity as expected; however, diffuse and particulate cellular and tissue staining for CNPS was detected in the brain parenchyma and the meninges in all cases. By quantitative analysis, the CNPS immunoreactive area ranged from 0.1 to 88 percent of tissue cross sectional area, and tended to be higher in brains of AIDS (median values from two sections ranged from 1 to 57 percent; mean, 26 percent) than in non-AIDS (0.1 to 40 percent; mean, 9.6 percent) patients. The proportion of CNPS immunoreactive area was positively correlated with the estimated number of CN. None (0/13) of the AIDS patients displayed significant inflammatory responses to CN, whereas most (7/8) non-AIDS patients showed granulomatous inflammatory responses. The phenotype of infiltrating lymphocytes was UCHL-1+/L26-/RC4-, thus consistent with activated T cells, both in AIDS and non-AIDS patients. Double immunolabeling studies revealed that tissue CNPS immunoreactivity was most often localized in macrophages and microglia, less frequently in reactive astrocytes and endothelial cells, but not in lymphocytes. This study demonstrates that CNPS can be detected not only in the serum and cerebrospinal fluid (CSF) of patients, but also in the affected tissue, most often localized in cells of mononuclear phagocyte system. Potential implications of these findings for the pathogenesis of CME are discussed.