The invention belongs to the field of medical preparations, and relates to an immunomodulator polypeptide slow-release microsphere preparation and a preparation method thereof. Particularly, the immunomodulator polypeptide comprises thymopentin, thymalfasin and thymosin beta4. The slow-release microsphere comprises 0.1-30% (w/w) of immunomodulator polypeptide, 60-80% of biodegradable high polymer material with biocompatibility, of which the molecular weight is 5,000-200,000 Dalton, and 0.1-20% of other pharmaceutical acceptable auxiliary materials on the basis of the total weight of the microsphere. According to the slow-release microsphere disclosed by the invention, the mean grain size is 5-60mu m; the encapsulation efficiency is greater than 90%; the slow release period of the slow-release microsphere can be up to a few days and months, the medication times is obviously reduced, the bioavailability is improved, the toxic and side effects of the medicine are reduced, and clinical treatment is facilitated. The product is good in production process repeatability and good in feasibility.