We used methenamine silver stains to retrospectively evaluate the prevalence of fungi and their associated inflammatory reactions in 63 patients with cystic fibrosis (CF) autopsied between 1982 and 1987. Fungi were detected in 13 patients (21%) who fell into three groups: respiratory tract colonization (five patients); localized infection (five patients); and disseminated infection (three patients). Hyphae consistent with Aspergillus sp were present in five patients; yeast-like cells and/or pseudohyphae consistent with Candida sp occurred in eight patients; and Histoplasma capsulatum produced fibrocaseous lymph node and splenic granulomas in one patient. Acute inflammation typified most fungal lesions, while bronchocentric granulomatosis affected one patient. Compared with patients with no fungi, those with fungi were more frequently treated with indwelling central venous catheters (P less than .05). Autopsy reports on 156 CF patients from 1964 to 1982 disclosed only one with disseminated mycosis (P less than .05). We conclude that stainable fungi can be found in CF patients at autopsy more frequently than previously realized. Fungi usually represent respiratory tract colonization or minimal localized infection, but the prevalence of fatal disseminated infection (4.8%) has also increased. Fungal infection in CF appears to be most closely associated with aggressive therapeutic intervention.