OBJECTIVE To compare the efficacy and safety of voriconazole with itraconazole as prophylaxis in leukemia patients. METHODS Open-label, randomized study. Patients with acute myelogenous leukemia or high-risk myelodysplastic syndrome undergoing induction chemotherapy or first salvage were eligible. Patients received voriconazole (400 mg intravenous (i.v.) every 12 h for two doses, followed by 300 mg BID) or itraconazole (200 mg i.v. twice daily for 2 days, followed by 200 mg i.v. daily). RESULTS A total of 127 patients were enrolled. Four were excluded because they did not receive study drug (n=3) or received two antifungal agents during the first week on study (n =1), leaving 123 patients for analysis. None of the 71 patients receiving voriconazole developed proven or probable invasive fungal infection, compared to two (4%) of the 52 patients receiving itraconazole (P=0.17). Drug discontinuation because of adverse events occurred in 15 patients (21%) receiving voriconazole and six (11%) receiving itraconazole (P=0.23). CONCLUSIONS Voriconazole is a good alternative for prophylaxis in patients with leukemia. Elevated baseline bilirubin levels were associated with a higher risk of side effects in patients receiving i.v. voriconazole or i.v. itraconazole. Monitoring of liver function and drug levels should be considered for some patients.