Objective：To analyze the differential expressions of peripheral serum protein in patients with metastatic and non-metastatic melanoma by proteomic technology and to explore its clinical significance in the treatment of patients with metastatic melanoma. Methods：Totally 101 patients were selected and divided into metastatic melanoma group（n=25） and control group（n=76，31 cases of non-metastatic melanoma and 45 healthy cases）. Seventy-three cases（18 cases of metastatic melanoma，20 cases of non-metastatic melanoma and 35 healthy cases） were randomly extracted as diagnostic model group，the rest 28 cases（7 cases of metastatic melanoma，11 cases of non-metastatic melanoma and 10 healthy cases） were used to verify for model group by blind tests. Matrix assisted laser desorption ionization time of flight mass spectrometry（MALDI-TOF-MS） was applied to test peripheral serum protein. Ciphergen pro－tein chips were used to analyze protein profiling. Results：Mass-to-charge ratios of peripheral serum of patients with metastatic mela-noma against that of control group were 2 598.33，3 646.79，4 605.48，8 603.10，7 756.64 m/z and 9 598.82 m/z. Differences in expres－sions of six protein peaks were statistically significant（all P=0.000）. Diagnostic model of metastatic melanoma was built according to the statics above. Sensitivity of diagnostic model group was 83.33% and specificity was 74.55%. In addition，validation groups were used for this model by blind tests. Sensitivity of metastatic melanoma was 71.43% and specificity was 74.55% based on the model. Conclusions：There are significant changes in expression profile of peripheral serum protein between patients with metastatic melanoma and controls；proteins with relative molecular mass of 1 528.33，2 046.79，3 685.48，4 392.10，5 756.64 m/z and 11 670.82 m/z can be used as biological markers in the treatment of early metastatic melanoma.