PURPOSE: To determine the optimal dose and duration of fluconazole antifungal prophylaxis therapy in bone marrow transplantation patients. SUBJECTS AND METHODS: Two hundred and fifty-three pediatric and adult bone marrow transplantation patients were randomly assigned to receive fluconazole 400 mg daily (high dose) or 200 mg daily (low dose) while they were neutropenic. After neutrophil recovery, patients were randomly assigned to receive maintenance therapy with either fluconazole (100 mg daily) or clotrimazole troches (10 mg 4 times daily) until 100 days after transplantation. Patients were monitored until 2 weeks after completion of early prophylaxis and to 100 days after transplantation. RESULTS: During the early prophylaxis phase, rates of yeast colonization and infections were similar in both treatment groups. By day 50, the incidence of Candida infections in the high-dose group was 4% (95% confidence interval [CI]: 1% to 7%; n 3 5), compared with 1% in the low-dose fluconazole group (95% CI: 0% to 3%; n 3 1; P 3 0.08). During the same period, the incidence of Aspergillus infections was 4% (95% CI: 1% to 7%; n 3 5) in the high-dose group and 2% (95% CI: 0% to 4%; n 3 2; P 3 0.33) in the low-dose group. During the maintenance prophylaxis phase, rates of yeast colonization and superficial infections were similar in the fluconazole and clotrimazole groups. Four patients developed systemic fungal infection in the maintenance phase (1 who received clotrimazole and 3 who received fluconazole). CONCLUSION: High-dose (400 mg daily) and low-dose (200 mg daily) fluconazole have similar efficacy in reducing the incidence of yeast colonization, superficial infection, and systemic infection in neutropenic pediatric and adult patients undergoing bone marrow transplantation. Rates of yeast colonization after neutrophil recovery were similar in patients treated with fluconazole or clotrimazole.