Update publication information. Uveitis and posterior scleritis are sight-threatening diseases with undefined pathogenesis, accurate diagnosis remains challenging. Here, two plasma-derived extracellular vesicle (EV) subpopulations, small and large EVs, were obtained from patients with uveitis and posterior scleritis and subjected to proteomics analysis alongside plasma. We identify 3,658 proteins, with 3,097, 3,312, and 2,820 quantifiable proteins for sEVs, lEVs, and plasma, respectively. The proteomes of the two EV subgroups differed significantly and were more highly correlated with disease development than that of plasma. Comprehensive bioinformatics analysis of the EVs and plasma highlighted a potential pathogenic mechanism for these diseases. Four potential biomarker panels for four diseases were identified and validated. We found a negative correlation between plasma endothelin-converting enzyme 1 levels and mean retinal thickness. This study provides a proteomic landscape of the molecular changes in plasma and EVs involved in four diseases, offers insights into their potential pathogenesis, and identifies valuable biomarker candidates.