Abstract: AIM　To optimize the preparation of sustained release microspheres (MS) using the biodegradable materials-poly(hydroxybutyrate-hydroxyvalerate)/D,L-polylactide blend as the carriers and diazepam (DZP) as a model drug. METHODS　The orthogonal test design was used to optimize the technology of preparation with good reproducibility. The surface morphology of the microspheres was observed by scanning electron microscope. The mean diameter and the size distribution of MS, drug release in vitro, stability and pharmacokinetics in rabbit were examined. RESULTS　The average particle size was (20.45±4.50) μm with over 88% of the MS being in the range of 15.5～35.2 μm; the drug loading and the incorporation efficiency were 16.95%±0.80% and 69.68%±1.13% respectively; The drug release behavior in vitro could be expressed by the following equation: Q=3.2916t+13.61 (γ=0.9827); Experiments in rabbits indicate that the area under the plasma concentration-time curve (AUC) was 2.35 times higher than that of DZP solution. The mean residence time (MRT) was 3.62 times longer compared with the original drug DZP solution. The microspheres were stable for 3 months at 4℃ and at room temperature. CONCLUSION　The technology of preparation was successful and DZP-PHBV/PLA-MS showed significant sustained release.