Supercritical fluid assisted atomization introduced by hydrodynamic cavitation mixer (SAA-HCM) was used to prepare chitosan microparticles with the well-defined spherical morphology and the controlled particle size distribution as a promising carrier for drug delivery system. Chitosan with different molecular weights (3 kDa, 50 kDa, 300 kDa) was successfully micronized, in which water was used as the solvent for 3 kDa chitosan, while 1.0% (v/v) acetic acid aqueous solution was used for 50 kDa and 300 kDa chitosan, respectively. The process parameters including operating pressure and temperature in the mixer, mass flow ratio of CO2/solution, precipitator temperature and solution concentration were explored to evaluate their influences on the morphologies and size distributions of precipitated particles. Results showed that particle size tailoring (ranging between 0.2 and 5 pm) could be achieved through modulation of the process parameters. After processing by SAA-HCM, Fourier transform infrared spectroscopy did not indicate significant change in the main structure of chitosan micropartides. Compared with raw materials, a decrease in crystallinity and thermal stability was observed for the SAA-HCM processed chitosan microparticles, as demonstrated by X-ray diffraction, thermogravimetric analysis and differential scanning calorimetry. (C) 2014 Elsevier B.V. All rights reserved.