The pathogenesis of cerebral infection after Cryptococcus neoformans fungemia in outbred mice was investigated. Confocal microscopy and cultures on ficoll-hypaque gradient-separated blood cells were used to detect yeasts in the cytoplasms of monocytes. In semithin brain sections, poorly capsulated yeasts were seen in macrophages in the leptomeningeal space, in monocytes circulating in leptomeningeal capillaries, or in the endothelial cells themselves, strengthening the hypothesis that monocytes and endothelial cells play key roles in the pathogenesis of cryptococcal meningitis. Similar fungal loads and cellular reactions were seen in mice and in 1 patient with acquired immune deficiency syndrome (AIDS), all with acute cryptococcal meningoencephalitis, and in mice and in 1 patient with AIDS, all with cured cryptococcal infection. Immunostaining revealed both the presence of cryptococcal polysaccharide in various brain cells and antigenic variability both from yeast cell to yeast cell and over time. Thus, our data established the relevance and interest that this experimental model has for investigation of the pathogenesis of human cryptococcal meningitis.