The aim of this study was to prepare dry powder inhalers (DPIs) containing amphotericin B-loaded solid lipid nanoparticles (AMB-SLNs) as an alternative approach for prevention of pulmonary aspergillosis. For solubilizing AMB in small amounts of organic solvents ion paired complexes were firstly formed by establishing electrostatic interaction between AMB and distearoyl phosphatidylglycerol (DSPG). The SLN formulations containing AMB-DSPG complexes were prepared using glycerol monostearate (GMS) as the lipid matrix and soybean lecithin and tween 80 as the surfactants by solvent emulsification-evaporation technique. The nanoparticles were optimized through a fractional factorial design. DPIs were prepared by lyophilization technique using lactose as the inhalational carrier and then after, the formulations were evaluated in terms of aerodynamic particle size distribution using an Andersen cascade impactor. The morphology of the particles was examined using scanning electron microscopy (SEM) and drug release profiles were evaluated. Following the statistical results, the particle size, Poly dispersity index (PdI), zeta potential, entrapment efficiency (EE%), and drug loading (DL%) of the optimized SLNs were 187.04 ± 11.97 nm, 0.188 ± 0.028, -30.16 ± 1.6 mV, 89.3 ± 3.47 % and 2.76 ± 0.32 %, respectively. Formulation containing 10% w/v of lactose with the calculated fine particle fraction value as 72.57 ± 4.33% exhibited the appropriate aerodynamic characteristics for pulmonary drug delivery. SEM images revealed de-agglomerated particles. release studies showed sustained release of AMB from the carriers and the release kinetics were best fitted to the first order kinetic model.