Background: The lack of effective serum and cerebrospinal fluid (CSF) biomarkers remains a barrier to early diagnosis and treatment of multiple sclerosis (MS). The study is to identify the diagnostic biomarkers of serum and CSF in patients who suffered MS. Methods: At first, we performed differential analysis of CSF and serum proteomics on control and relapse-remitting multiple sclerosis (RRMS) patients. Secondly, CSF and serum's differential proteins were compared, in order to identify the significative proteins. Finally, Kyoto Encyclopedia of Genes and Genomes (KEGG) and Gene Ontology (GO) analysis were performed on the differential proteins in serum and CSF respectively to clarify their common biological functions and pathways. Results: At the first step, in CSF, 73 proteins were significantly differentially expressed in the RRMS set compared with the controls. In serum, 22 proteins were differentially expressed. Secondly, we found MMP2 C8G and CFH were the same high expression trend in CSF and serum. Finally, we found the differential proteins in serum and CSF are mostly participated in biological processes: immuno-inflammatory response, neuronal development, cell adhesion and signaling. Conclusion: MMP2, C8G and CFH may participate in the pathogenesis of RRMS, which are the potential diagnostic biomarkers of the disease.Copyright © 2022 Liu, Wang, Li, Li, Han, Qi, Wang and Gao.