A double-blind trial was carried out to study the effect of oral administration of fluconazole in the treatment of Candida-associated denture stomatitis. The study group consisted of 38 denture stomatitis patients who harbored yeasts, predominantly Candida spp., in significant numbers as determined by culture from the lesions. Half of the patients received 50 mg of fluconazole per day orally for 14 days, and the other half received placebo capsules. The following parameters were studied: degree of palatal erythema, presence of yeast cells (by plate count and microscopy of smears), identification to the species level of dominant yeast organisms, biotyping of Candida albicans, and treatment-related side effects. A significant reduction of erythema was seen after treatment with fluconazole, but the inflammation showed partial relapse 2 to 4 weeks after treatment was terminated. Reduced soreness of the oral mucosa was reported by six of the patients in the fluconazole group. No significant clinical or yeast flora changes were observed in the placebo group. Extensive changes in the yeast flora were observed in the fluconazole group, both in quantity and in composition of yeast species and C. albicans strains (biotypes), which perhaps indicated differences in pathogenicity and fluconazole susceptibility among various yeast species and C. albicans strains. Fluconazole did not produce any changes in the results of blood and urine analyses. The results indicate that fluconazole is a safe and well-tolerated antimycotic drug. The transient clinical and antimycotic effect may have been due in part to the possibility that therapeutic concentrations of the drug were not reached beneath the fitting denture surface and within the denture plaque.