Complications from pathologic myopia (PM) are a major cause of visual impairment and blindness. However, an efficient clinical therapeutic strategy for PM is still lacking. The aim of this study was to quantitatively compare the proteomic profiles of aqueous humor between PM and non-PM cataract patients. Twenty aqueous humor samples from each group were analyzed with label-free quantitative proteomic analysis to identify the differentially expressed proteins for function enrichment analyses and protein-protein interaction network construction. Hub protein was validated with ELISA using an independent cohort consisting of 20 samples from each group and its receiver operating characteristic (ROC) curve analysis was conducted. A total of 583 proteins were identified and 101 proteins were found to be differentially expressed, including 63 up-regulated proteins and 38 down-regulated proteins. The bioinformatics analysis suggested that PM is closely associated with immunity and inflammation interactions, and remodeling of extracellular matrix. Apolipoprotein A-I (ApoA1) was enriched as the hub protein of the network with the highest score, degree and centrality. ROC analysis showed that ApoA1 could distinguish PM from controls with an area under the curve of 0.963 (p < 0.001). The findings could provide potential clues for further study on the molecular mechanisms and developing new treatments for PM, especially related to immunity and inflammation interactions. ApoA1 may be a potential key protein and therapeutic target in human PM. SIGNIFICANCE: It is important and urgent to discover the mechanisms of pathologic myopia (PM) to inhibit its progression. This study applied the quantitative proteomic analysis to study aqueous humor from patients with or without PM, aiming to discover dysregulated proteins related to PM. Our results suggested that those dysregulated proteins are closely associated with immunity and inflammation interactions, and remodeling of extracellular matrix. The findings from this study could provide potential clues for further research on the molecular mechanisms and developing new treatments for PM, especially related to immunity and inflammation. ApoA1 may be a potential key protein and therapeutic target in human PM.Copyright © 2019. Published by Elsevier B.V.