Add Publication. Neuromyelitis optica spectrum disorder (NMOSD) and myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD) are two types of autoimmune-mediated central nervous system (CNS) inflammatory demyelinating diseases that have similar clinical manifestations but with different pathogenesis and prognosis. Here we reported on a serum differential proteomic analysis of the patients with the two diseases. Sera of 25 Aquaporin-4 (AQP4)-IgG+ NMOSD patients, 16 MOGAD patients and 8 healthy people were submitted to shotgun analysis using nano-LC-MS/MS. Totally 584 non-redundant proteins were identified, among which 340 proteins were detected in at least three samples per group. Statistical analysis revealed 40 proteins have significant difference in at least one pair-comparison (fold change >=1.2 or <=0.83 and multi-sample test ANOVA-q <0.05). Further, 38 proteins were detected only in the patient groups and not in the healthy control group. Bioinformatic analysis on these 78 proteins revealed that disturbance on immune system, hemostasis processes and carbohydrate metabolism occurred in both diseases, but with different mechanisms. We believe this work could provide useful information to improve the understanding of the mechanisms of NMOSD and MOGAD and suggest potential diagnostic markers and treatment targets.