The objective of these studies was to demonstrate that direct administration of itraconazole nanoparticles to the lung is more efficacious than conventional high orally administered doses of itraconazole. Nebulized colloidal dispersions of crystalline itraconazole (cITZ) or amorphous itraconazole (aITZ) using a cascade impactor indicated similar mass median aerodynamic diameters (MMADs) of 2.7 and 2.8 µm, and fine particle fractions (FPFs) of 76 and 85% respectively. Lung concentrations of itraconazole in a murine model followed by pharmacokinetic analysis following pulmonary administration of cITZ or aITZ, indicated similar Cmax values and lung retention times. Repeated oral administration of commercially available Sporanox® Oral Liquid [SOL] or pulmonary dosing (aITZ) BID up to 12 days, indicated higher lung concentrations after pulmonary administration (mean trough level = 2.30 µg/g). compared to that of the orally administered drug (mean trough level = 0.17 µg/g). Finally, a survival study of mice challenged with Aspergillus flavus, showed that there was a significant improvement in survival in mice when they received the pulmonary formulations of cITZ and a aITZ compared to SOL and control groups. In conclusion, targeted pulmonary administration of the antifungal drug itraconazole shows a clear therapeutic advantage with improved survival rates compared to commercially available orally administered Sporanox®.