To evaluate and compare in vivo the protective efficacy of unilamellar liposomal amphotericin B (L-AmB) with that of deoxycholate amphotericin B (D-AmB) in experimental endocarditis. In the rabbit model of experimental Aspergillus fumigatus endocarditis, two doses of each antifungal agent (1.5 mg/kg each) were administered intravenously at 4 hours and at 30 minutes before challenge with an inoculum of A. fumigatus. Three days later, the animals were sacrificed, and the aortic vegetations were analyzed. All 19 animals that did not receive chemoprophylaxis acquired endocarditis. In contrast, endocarditis developed in 2 of 10 animals pretreated with D-AmB (P<0.01) and 3 of 8 animals pretreated with L-AmB (P<0.01). Both D-AmB and L-AmB prevented the development of endocarditis due to A. fumigatus and decreased the concentration of fungi in the aortic vegetations by more than 1 log 10 . In the rabbit experimental model of Aspergillus endocarditis, D-AmB and L-AmB were equally effective in reducing the incidence of the infection and the tissue burden of fungi.