Outbred ICR mice were rendered neutropenic, infected intravenously with Fusarium solani and treated orally with voriconazole. When given alone, voriconazole was not protective up to 40 mg/kg/day. When grapefruit juice was administered before infection, mice were protected by voriconazole. The mechanism may be inhibition of gut mucosal cytochrome enzymes that rapidly degrade voriconazole in the mouse. These murine studies support expansion of voriconazole therapy in other highly resistant systemic mycoses.