Abstract: OBJECTIVE To optimize the preparation technology of florfenicol sustained release microspheres by simple coacervation method. METHODS Microspheres were prepared by simple coacervation method. The effects of influences factors such as the ratio of core to material, encysted pH and stirring speed, on overall desirability (OD) of diameter and entrapment efficiency were investigated by central composite design and response surface method. The data were imitated using second-order polynomial. Microspheres prepared by optimal condition were releasing in vitro in artificial body fluid. RESULTS The optimal conditions were as follow: the ratio of core to material as 0.375, encysted pH as 4.8, and stirring speed as 615 r·min^-1. The microspheres prepared by optimal condition were round and uniform with particle size of 40~50 μm. The entrapment efficiency was 57.45% and the drug loading reached 17.52%. The microspheres had good slow-release characteristics in Hank’s artificial body fluid. CONCLUSION Microspheres prepared by optimal method load more drug with good shape, and the slow-release characteristics are good.