Schizophyllum is an important genus of basidiomycetes that, apart from being of genetic and biotechnological interest, is also reported to be a plant and animal pathogen. Schizophyllum commune is the best-known species and the only one reported from clinical specimens thus far, being recovered mainly from the respiratory tract. The aim of this study was to determine the species diversity of 23 clinical isolates of Schizophyllum from the United States using multilocus phylogenetic analysis and their in vitro susceptibilities to six drugs. The markers used for sequencing were the internal transcribed spacer (ITS), a portion of the nuclear large subunit (LSU) of ribosomal DNA, the RNA polymerase II second-largest subunit (RPB2), and the translation elongation factor 1␣ (EF-1␣) gene. The analyses revealed that 22 of the clinical isolates were in the Schizophyllum radiatum clade with high support values and 1 isolate was in the S. commune clade. This is the first report of this species in clinical samples. The two species mentioned above showed very similar morphological features in culture (i.e., white, cottony, unsporulated colonies composed of hyphae with clamp connections), making morphological discrimination between the two impossible. An epitype is designed for S. radiatum, and its sequences have been deposited in GenBank. The antifungal that showed the greatest in vitro activity against the strains tested was shown to be amphotericin B. In general, the strains of S. radiatum showed higher MICs than S. commune. S chizophyllum (Schizophyllaceae, Agaricales) comprises one of the most commonly found mushrooms on the planet (1). The most common species of the genus is Schizophyllum commune, a ubiquitous fungus well-known as a wood decay organism able to cause white rot (1, 2) but also by its biotechnological applications (3). It has been used as an ethanol producer (4), and some of its metabolites have anticancer (5) and antimicrobial (6, 7) properties. It also has been studied for many years as a model for understanding mating interactions (8, 9). In recent years, S. commune has become clinically relevant as an etiological agent of respiratory infections in humans (10-15). However, it has been reported to be an etiological agent of other types of infections and conditions, such as a brain abscess (16, 17), meningitis (18), an eye infection (19), palate ulceration (20), and onychomycosis (21). Infections have also been reported in other mammals (22-24) and in both immunocompromised and immunocompetent individuals (25,26).The most effective treatment options for infections by S. commune are yet to be determined, although various treatment modalities have been used (14,(25)(26)(27)(28)(29). Most susceptibility patterns for these fungi are restricted to individual cases; however, studies by Gonzalez et al. (30) and Chowdhary et al. (31) with 5 and 26 strains, respectively, indicated that amphotericin B (AMB), itraconazole (ITC), and voriconazole (VRC) had good in vitro activity against the isolates tested, while elev...