PURPOSE. This study investigated the proteomic landscape of exfoliation glaucoma to find potential biomarkers. METHODS. The study enrolled 34 patients diagnosed with either exfoliation syndrome with/without glaucoma or age-related cataract. Plasma proteins were analyzed through mass spectrometry and Mendelian randomization (MR) based on data from deCODE, FinnGen, Atherosclerosis Risk in Communities (ARIC), eQTLGen, and UK Biobank (UKB) cohorts to infer relationships. RESULTS. Among 2025 plasma proteins analyzed, 130 were differentially expressed in the exfoliation glaucoma group, which exhibited elevated intraocular pressure. Our proteomics data suggested that infection, immune responses including intestinal immune network, endocrine hormones, and complement and coagulation cascades are involved in the development of exfoliation glaucoma. Notably, there was a significant correlation between SVEP1 and exfoliation glaucoma (odds ratio [OR] = 1.20, 95% confidence interval [CI] = 1.10 to 1.31, P = 0.0000428), with findings corroborated in an independent cohort. Further analysis predicted a protective role of LOXL1-AS1 in exfoliation glaucoma through its regulation of SVEP1 expression. In MR phenome-wide association studies, SVEP1 was associated with complications of exfoliation glaucoma. After multiple testing corrections, there was a tendency for SVEP1 to be associated with glaucoma (OR = 1.14, 95% CI = 1.11 to 1.16, P = 0.0000003) and type 2 diabetes (OR = 1.07, 95% CI = 1.05 to 1.08, P = 0.0000067). CONCLUSIONS. Plasma proteomic analysis reveals that high expression of SVEP1 is a risk factor for exfoliation glaucoma, which potentially affects diabetes and is affected by estradiol or LOXL1-AS1. However, further research is needed to establish causality.