Objective: To analyze the serum protein markers in diabetic nephropathy (DN) patients with poor prognosis in stage III-IV using SELDI-TOF-MS technique. Methods: 50 DN patients in stage III-IV were divided into poor prognosis group (n=27) and good prognosis group (n=25); And 25 health examinees in the same period were tanken as control (normal control group). The serum of all the subjects were obtained; SELDI-TOF-MS was used to establish the protein fingerprint and analyze the differential protein among different groups. Results: There were two highly expressed differential proteins between the good prognosis group and the normal control group; There were four highly expressed differential proteins between the good prognosis group and the poor prognosis group; There were five highly expressed differential proteins between the poord prognosis group and the normal control group. Conclusions: The protein with a mass-charge ratio (M/Z) of 3125.76Da may be the serum protein marker of DN patients with poor prognosis in stage III-IV.