Pulmonary aspergillosis is a serious opportunistic disease in patients with immune suppression. Prophylactic measures would be highly beneficial because treatment often fails after infection occurs. The principle objective of this study was to evaluate the prophylactic efficacy of aerosolized liposomal (AmBisome) and non-liposomal (Fungizone) amphotericin B in a murine model. Immunocompromised mice were treated prophylactically for 3 days with AmBisome or Fungizone using a small particle aerosol generator. Intranasal challenge was with a high (10(8)), medium (10(7)), or low (10(6)) level of Aspergillus fumigatus spores. AmBisome nebulized more uniformly, resulting in very consistent chamber air concentrations. Total dose, however, was nearly the same for each formulation. Survival was prolonged in animals treated with both formulations at the 10(8) and 10(7) challenge levels. Quantitative lung cultures showed that organisms were completely cleared from the lungs in the low challenged group, with both formulations, whereas the high challenge proved overwhelming for both formulations. With the middle challenge, however, AmBisome cleared 80% of the lungs, whereas Fungizone cleared none. Lung drug retention of AmBisome treated animals was more than eight times higher than Fungizone at the time of challenge. BUN and creatinine values in animals treated with both formulations were not elevated. These results suggest that AmBisome is more effective than Fungizone when given as a prophylactic aerosol in this model.