Schizophyllum commune has recently emerged as a causative agent of human mycosis, but the details of its virulence are not yet known. To elucidate the pathogenicity of S. commune, a murine model of invasive pulmonary infection was established. ICR mice, not immunosuppressed or immunosuppressed by cortisone acetate, were infected with S. commune by intratracheal inoculation with agar beads containing the basidiospores. All immunosuppressed mice died within 2 weeks. Pathology examination revealed massive mycelial invasion into the lungs, penetration into adjacent vessels, and systemic dissemination, suggesting much higher virulence of this fungus than was previously estimated. This is the first murine model of pulmonary infection by S. commune, which we believe can be of assistance during subsequent investigations of this infection.