Ninety patients were studied in a controlled, randomized fashion to evaluate the effectiveness of topical 5-fluorouracil in reducing the recurrence rate of human papillomavirus-associated lesions of the vulva and vagina. Following complete ablation of the lesions by one or more treatment modalities, 45 patients applied a single dose of 5% 5-fluorouracil cream biweekly to the vagina and/or vulva for at least six months. Forty-five patients used no prophylactic 5-fluorouracil cream. Patients in both groups were comparable with regard to race, age, and immune status, as well as the number, location, duration, clinical appearance, histology, and prior treatment of the lesions. Six patients (13%) with 5-fluorouracil prophylaxis and 17 (38%) without additional treatment (P less than .01) developed recurrent lesions during a follow-up time of nine to 22 months (mean = 14.4 months). Maintenance therapy with 5-fluorouracil was most effective in women with multiple lesions, multiple organ involvement, or with a depressed immune system.