An experimental model for the study of paracoccidioidomycosis was established in BALB/c mice. Both normal and athymic nu/nu animals were challenged intraperitoneally and intratracheally with yeastlike cells of Paracoccidioides brasiliensis. After challenge, all immunologically intact (+/+) mice survived, whereas nu/nu mice gradually succumbed. The latter had focal peritoneal, liver, spleen, and lung lesions consisting of P. brasiliensis with inflammation, polymorphonuclear leukocytes, monocytes, and histiocytic reactions, but no granuloma formation. Thymus transplantation heightened resistance of nu/nu mice to P. brasiliensis. These studies indicate that the nu/nu mouse develops progressive lethal paracoccidioidomycosis after intraperitoneal and intratracheal challenge, and that thymus-dependent immune mechanisms mediate host defense.