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Alterations in the sera proteins between patients with Primary Open-Angle Glaucoma (POAG), Pseudoexfoliation Glaucoma (PEXG), and healthy controls were identified through a proven approach utilizing equalization of high-abundance serum proteins with ProteoMiner™, two-dimensional fluorescent difference gel electrophoresis (2D-DIGE), MALDI-TOF/TOF, and nanoLC-MS-MS. Quantitative immunoassays of the 17 most-differentially-altered proteins identified in this analysis confirmed that they were also over expressed in the intact serum of newly recruited glaucoma patients. Overall, this report identifies a panel of candidates for glaucoma biomarkers and supports their further validation in large population studies. Additionally, functional pathway analysis of these candidate proteins suggested that they are part of a network linked to regulating immune and inflammatory-related processes. The data have been deposited to the ProteomeXchange with identifier PXD000198. Biological significance POAG and PEXG are major causes of age-related blindness in the world; however, treatment can be very effective if they are identified early on in the progression. Genetic linkage studies can only explain a limited number of cases, suggesting that these forms of glaucoma are multigenic in nature. Other important factors, such as modifier genes, epigenetic influences, environmental and dietary agents, and inflammatory and oxidative effects are also believed to affect the development of these diseases. The characterization of metabolic and/or proteins changes, for example in bodily fluids, before the clinical manifestation of glaucoma is of considerable relevance for its early diagnosis. In the present work, identification of over-expressed proteins in serum of glaucoma patients (POAG and PEXG) linked to immune and inflammatory processes supports the finding that changes in these pathways also manifest systemically in patients with these pathologies. This study provides a new basis to validate the identified proteins as biomarkers of glaucoma in a large-scale-multiplexed screening in sera.