A novel self-developed technique ultra-fine particle process system (UPPS) was employed to develop sustained-release metoprolol tartrate (MT) microspheres for oral administration. Ethyl cellulose (EC) was selected as matrix, and Eudragit RS 100 was induced to regulate the viscosity and release profile of the MT microspheres. Single factor tests and L9 (3³) orthogonal test were performed to optimize formulation, and the in vitro drug release, particle size, bulk density, flowability, scanning electron microscope (SEM), differential scanning calorimetry (DSC) and powder X-ray diffraction (XRD) were characterized for the MT microspheres. The optimal formulation used for making microspheres was a dispersion with 5% (w/v) EC and 2% (w/v) Eudragit RS 100 in 80% (v/v) ethanol solution, and the drug MT content was 20% based on solid weight in the dispersion. The MT microspheres obtained by UPPS were approximate spheroidal solid particles with particle size in the range of 80 to 120μm and bulk density of 0.134±0.003g/cm³. Compared with blank microspheres, the MT microspheres possessed more round structure with uneven surface and better flowability due to their different formation process. It was indicated that MT was in amorphous form in the obtained microspheres and had no interactions with excipient by the DSC and XRD. 24h sustained-release microspheres were successfully achieved by UPPS for water-soluble MT. In addition, the in vitro drug release behaviors of the MT microspheres were similar in different release medium, indicating they would not be affected by pH value variation in gastrointestinal tract. All the result proved that the UPPS is a novel and promising technique for preparing sustained-release microspheres, and may be suitable for industrial production due to its successive and controllable step in preparation.