Although considered nonpathogenic, Saccharomyces cerevisiae is being encountered more frequently in the clinical setting. To assess pathogenic potential, 13 clinical isolates, 10 nonclinical isolates, and 5 constructed strains of S. cerevisiae were analyzed. All were S. cerevisiae by biochemical profiles, sporulation, or genetic evidence. Intravenous inoculation of yeasts into CD-1 mice showed that some clinical isolates proliferated in the brain (5-fold) but nonclinical isolates were cleared (1000-fold) by day 7 after infection. Comparison of burdens with those of YJM128 (clinical) and Y55 (laboratory strain) revealed three virulence groupings: virulent, those greater than or equal to YJM128 (5 clinical and 2 genetic constructs); intermediate virulent, those less than YJM128 and greater than Y55 (5 clinical, 3 genetic constructs, and 4 nonclinical); and avirulent, those less than or equal to Y55 (1 clinical and 6 nonclinical). Genetic crosses indicated that virulence was a dominant trait. Growth of various isolates at 37 degrees C and 39 degrees C indicated that temperature is associated with but not solely responsible for differences in virulence. These data demonstrate that some clinical isolates of S. cerevisiae can proliferate and resist clearance in vivo and support the potential of S. cerevisiae as a cause of clinical disease.