Many Histoplasma capsulatum strains have α-(1,3)-glucan in their ceil walls and spontaneously produce variants that lack this polymer. The variants, in contrast to the parents, exist in aberrant shapes within macrophages. Here, the ultrastructure of the parental and variant cell walls was examined. All yeasts had identical electron-lucent, thick walls when grown in broth culture. However, ingestion by either macrophases or hamster trachea epithelial (HTE) cells caused the wails of variants to become electron-dense, thin, and sinuous. Parental strains remained unchanged in macrophages. Within HTE cells inoculated with parental strains, some organisms retained a thick wall and α-(1,3)-glucan but appeared to be degrading. In contrast, apparently intact intracellular yeasts had thin, wavy walls lacking α-(1,3)-glucan. A microenvironment within HTE cells that is unfavorable for the parental phenotype may trigger this ultrastructural change, potentially explaining why only variant yeasts are harvested from such cultures.