Despite the worldwide distribution and prevalence of Schizophyllum commune, an emerging basidiomycetous pathogen, human infections occur only rarely. We describe the first well-documented pulmonary infection caused by S. commune which disseminated to the brain of a 58-year-old patient undergoing empiric corticosteroid therapy. Magnetic resonance imaging scans revealed ring-enhancing masses. Histologic examination of biopsy tissue from lungs and brain showed hyaline, septate, branched hyphae with clamp connections. Cultures of the lung tissue grew S. commune, which produced numerous, characteristic flabelliform and medusoid fruiting bodies on Czapek's agar. The isolate was susceptible to amphotericin B (MIC, < 0.03 microgram/ml) and fluconazole (MIC, 8 micrograms/ml). Despite treatment with antifungal and antibacterial agents, the patient developed progressive pulmonary failure and bacterial sepsis and died.