This study was to prepare polycaprolactone (PCL) nanoparticles. The biodegradable PCL was used as the carrier, and Azithromycin (AZM) was used as the model drug. AZM-PCL nanoparticles (AZM-PCL-NPS) were prepared by desolvation method. The effect of preparation condition: concentration of PCL, molecular weight of PCL, organic solvents, dosage ratio and so on, were specially noted and compared. A homogeneous size distribution and good dispersion were observed, the average diameter was around 70~400 nm, and the distribution index was 0.036~0.136. The drug loading reached 27.69 %, and the efficiency of encapsulation reached as high as 93.25%. The results were better than the other similar researches, this preparation way was successful.