The ability of bronchoalveolar macrophages from normal, diabetic, and cortisone-treated mice to inhibit spore germination and kill fungal spores in vivo was investigated. The data indicated that the normal host controls different fungal infections in the lungs by different mechanisms. Prevention of mucormycosis required inhibition of fungal spore germination by alveolar macrophages. In contrast, pulmonary defense against aspergillosis depended on early killing of conidia by alveolar macrophages and not on inhibition of germination by bronchoalveolar macrophages. Bronchoalveolar macrophages in diabetic and cortisone-treated animals allowed fungal spore germination, thereby permitting infection by Rhizopus oryzae. In the cortisone-treated mouse, bronchoalveolar macrophages did not kill fungal conidia and progressive infection by Aspergillus fumigatus occurred. Fungicidal activity of bronchoalveolar macrophages was measured with a new in vivo killing assay.