The present study was aimed at the preparation, characterization, and evaluation of the performance of amphotericin B (AmB)-loaded aerosolized liposomes and emulsomes (core composed of solid lipid surrounded by phospholipid bilayers) for their selective presentation to lungs (alveolar macrophages), as this is the densest site of aspergillosis infection. Liposomes and emulsomes were modified by coating them with alveolar macrophage-specific ligands (O-palmitoyl mannan, OPM) and also with monoclonal antibody EBA-2. The prepared formulations were characterized in vitro for vesicle size, zeta potential and percent drug entrapment. We evaluated the therapeutic efficacy of the novel site-specific targetable lipid-based delivery systems in experimental pulmonary aspergillosis. Immunosuppressed rats with pulmonary aspergillosis were given 1 mg/kg of aerosolized liposomal and emulsomes formulations of AmB once by using an ultrasonic jet nebulizer on the third day after infection. The concentrations of AmB in lung were higher in surface modified liposomes and emulsomes than those of plain counterparts. Changes in lung histopathology were also assessed. Further, scintigraphy was also carried out using 99mTc labeled liposomes. From those results it was concluded that radiolabeled liposomes could be used for in vivo imaging of the infection site, and that site directed system(s) based on OPM/mAb coating exhibited great potential in targeted antifungal chemotherapy.