The large surface area, good vascularization, immense capacity for solute exchange and ultra-thinness of the alveolar epithelium are unique features of the lung facilitating systemic drug delivery via pulmonary administration. The efficacy and safety of many new and existing inhaled therapies may be enhanced through advanced controlled-release systems by using polymer particles. Poly (D,L-lactic-co-glycolic acid) (PLGA) is well known by its safety in biomedical preparations which has been approved for human use by the FDA. The optimum aerodynamic particle size distribution for most inhalation aerosols has generally been recognized to be in the range of 1-5 microns. PLGA microspheres, therefore, were prepared by a developed oil-in-oil solvent evaporation method and characterized. A four-factor, three levels Box-Behnken design was used for the optimization procedure with temperature, stirring speed, PLGA and surfactant concentration as independent variables. Particle size and polydispersity of microspheres were considered as dependent variables. PLGA microparticles were prepared successfully in desired size for pulmonary delivery by solvent evaporation method. It was found that the particle size of microspheres could be easily controlled. It was also proved that response surface methodology could efficiently be applied for size characterization and optimization of PLGA microparticles for pulmonary drug delivery.