Azithromycin loaded microspheres with blends of poly-l-lactide and ploy-D,L-lactide-co-glycolide as matrices were prepared by the atmosphere-solvent evaporation (ASE) and reduced pressure-solvent evaporation (RSE) method. Both the X-ray diffraction spectra and DSC thermographs demonstrated that poly-L-lactide existed in a crystalline form in the ASE microspheres, while an amorphous form was present in the RSE formulations. Besides, solvent removal at atmosphere gave microspheres of porous and rough surfaces, but smooth surfaces appeared in the RSE microspheres. The incorporation efficiency as well as the burst release (cumulative release in the first 24h) in the ASE formulations was 39.94 ± 1.18% and 23.96 ± 2.01% respectively, yet the encapsulation efficiency of the microspheres fabricated under 385 mmHg was high up to 57.19 ± 3.81% and the burst release was 4.12 ± 0.15%. The in vitro drug release studies indicated that the ASE microspheres presented a zero-order profile; while the RSE formulations followed first-order kinetics. Other factors including solidification time, temperature, drug to polymer ratio and pH value of the continuous phase could also influence the physicochemical characteristics and release profiles of microspheres. In conclusion, the overall improvement of microspheres in appearance, encapsulation efficiency and controlled drug release through the RSE method could be easily fulfilled under optimal preparation conditions.