OBJECTIVE Candida vaginitis is currently treated with a wide range of intravaginal preparations usually prescribed over several days. Fluconazole with its marked activity against Candida species and favorable pharmacokinetics offered a safe, effective, and convenient alternative to topical therapy in a single-dose regimen. METHODS We conducted a multicenter, randomized, prospective, single-blinded study of 429 patients with acute Candida vaginitis, comparing the efficacy and safety of a single oral 150 mg dose of fluconazole with 7-day clotrimazole 100 mg vaginal treatment. Posttherapy evaluations and mycologic eradication rates were conducted. RESULTS No statistically significant differences were seen between fluconazole and clotrimazole in the clinical, mycologic, or therapeutic responses. At the 14-day evaluation clinical cure or improvement was seen in 94% of fluconazole-treated patients and 97% of clotrimazole-treated patients. Mycologic and therapeutic cures were seen in 77% and 76% of the fluconazole and 72% of the clotrimazole groups, respectively. At the 35-day evaluation 75% of both groups remained clinically cured, and 56% of the fluconazole and 52% of the clotrimazole group were considered therapeutic cures. In both treatment groups patients with a history of recurrent vaginitis (33/84) compared with those without a history of recurrent vaginitis (177/266) were significantly less likely to respond clinically and mycologically (p < 0.001). Twenty-seven percent of the fluconazole-treated patients and 17% of the clotrimazole-treated patients reported mild side effects only. CONCLUSIONS Fluconazole administered as a single 150 mg oral dose proved to be as safe and effective as 7 days of intravaginal clotrimazole therapy for Candida vaginitis. Therapy of vaginitis should be individualized, taking into consideration severity of disease, history of recurrent vaginitis, and patient preference.