The supercritical fluid expansion depressurization (SFED) process is a novel technique proposed recently to prepare microparticles with narrow size distribution. In this work, Erythromycin microparticles were precipitated successfully from ethanol by SFED process. The spherical or approximately spherical particles with diameters less than 3 mu m were obtained. The influences of the operation parameters, including the pressure and the ternperature in the mixing vessel, the solution concentration, the Solution feed rate and the temperature in the precipitator, on the particle morphology, size and size distribution were investigated in detail. The results show that the pressure in the mixing vessel and the solution feed rate are two most effective operation parameters while the solution concentration is the next. The temperatures in the mixing vessel and the precipitator have little effect on the particles, but they have great influence on the yield of the final product. The erythromycin microparticles with narrow size distribution can be prepared by SFED process and the particle morphology, size and size distribution can be controlled by adjusting operation parameters. The optimal operation parameters obtained in this work for preparing erythromycin microparticles are: the pressure of 10 MPa and the temperature of 70 degrees C in the mixing vessel, the solution feed rate of 9 ml/min, the solution concentration of 15 mg/ml and the precipitator temperature of 70 degrees C. (C) 2006 Elsevier B.V. All rights reserved.