A prospective, randomized, double-blind trial compared the efficacy and safety of a new one-dose clotrimazole regimen and placebo. Twenty-six patients with clinically and mycologically proven vulvovaginal candidiasis received either a 500-mg tablet of clotrimazole or a placebo. Follow-up visits were performed approximately one week and one month after treatment. Efficacy was evaluated in 23 patients. There was a highly significant difference in clinical and mycological responses to the two regimens (P = 0.0001, Fisher's exact test). Nine (90%) of the ten patients in the clotrimazole group showed mycological and clinical clearance of infection one month after treatment, while all 13 patients who had received placebo were classified as treatment failures at the first follow-up visit and were dropped from the study at this point. No patients experienced adverse effects attributable to clotrimazole or the placebo. The findings indicate that a single 500-mg tablet of clotrimazole is effective and safe in the treatment of vaginal candidiasis and suggest that the efficacy and safety of the one-dose regimen are comparable to those of more prolonged courses with the 100-mg tablet of clotrimazole. The convenient one-dose regimen promises to eliminate the widespread problem of patient noncompliance, especially when the tablet is inserted by the physician at the time of diagnosis.