Vaginitis due to Saccharomyces species is extremely rare. Nine patients with 20 vaginal isolates of Saccharomyces cerevisiae who presented with either asymptomatic vaginal colonization or symptomatic vaginitis indistinguishable from that caused by Candida albicans are described. All patients had a history of chronic or recurrent vaginitis, and all but two had systemic or local predisposing factors. In vitro tests of antimycotic sensitivity revealed reduced susceptibility of S. cerevisiae to the majority of available azole agents, with outright resistance to fluconazole. In accordance with these findings, the clinical response to conventional topical and oral antimycotic drugs was frequently suboptimal and incomplete. Electrophoretic karyotyping of strains revealed several distinct types of S. cerevisiae; this information permitted both longitudinal follow-up and differentiation of relapse from reinfection. In three patients with recurrent vaginitis, a unique epidemiological relationship was documented between S. cerevisiae and Torulopsis glabrata, another unusual and resistant vaginal pathogen. Isolation of S. cerevisiae from the vagina of symptomatic patients should not be ignored; treatment of vaginal infection with this yeast requires selected, often prolonged therapy.