Left-sided Aspergillus fumigatus endocarditis was established in the guinea pig heart by catheterization and inoculation with conidia via a tributary of the femoral vein. This animal model was used to compare the efficacy of the triazole antifungal agents voriconazole (UK-109,496) and itraconazole. In the prophylaxis experiments, voriconazole at a dosage of 10 mg/kg of body weight given intraperitoneally twice daily prevented A. fumigatus endocarditis in all but 1 animal (11 of 12 animals were cured). Itraconazole did not prevent Aspergillus endocarditis when it was given at the same dosage and by the same route (0 to 12 animals were cured). In the treatment experiments with 10 animals per group, voriconazole at 10, 7.5 and 5 mg/kg given orally twice daily for 7 days produced cure rates of 100, 70 and 0%, respectively. In contrast, itraconazole at 10 mg/kg given orally twice daily did not cure A. fumigatus endocarditis in the guinea pig. It is concluded that voriconazole is highly efficacious in the prevention and treatment of Aspergillus endocarditis in the guinea pig and is superior to itraconazole in these respects.