Purpose: Recent studies suggest that glaucoma may share common pathogenic mechanisms with Alzheimer's disease. To test this hypothesis, we investigated the correlation between glaucoma and amyloid-beta(42) (A beta(42)) concentration in human samples of aqueous humor (AH). Methods: Eighty-one candidates for cataract or glaucoma surgery were consecutively enrolled, with a median age of 77 years; of these, 32 subjects were affected by glaucoma and 49 were controls. Before surgery, each patient received an ophthalmological examination including biometry, intraocular pressure (IOP) measurement, fundus photography, and determination of the mean thickness of the ganglion cell complex (GCC) and/or retinal nerve fiber layer. During the surgical procedure, an AH sample was collected and immediately processed for total protein (TP) and A beta(42) evaluation. Results: A beta(42)( )levels were not statistically different between the glaucomatous and control samples, but a significant increase in TP concentration was found in the AH of glaucoma patients compared with controls (P = 0.02). In addition, positive correlations were observed between TP and A beta(42) (r = 0.51; P <0.0001), between TP and IOP (r = 0.44; P <0.0001), and between A beta(42) and IOP (r = 0.22; P = 0.033). Conclusions: Our results indicate that an increased protein concentration in the AH could play a role in the pathogenesis of glaucomatous disease. Translational Relevance: This study strongly supports the hypothesis that increased TP in the AH may have a pathogenic role in glaucoma. Further investigations are needed to clarify whether the protein enhancement represents a causative factor and whether it can be used as a marker of disease or as a novel therapeutic target.