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Glycosaminoglycans (GAGs) are structurally heterogeneous negatively charged polysaccharides. Endothelial GAGs, also known as glycocalyx, are involved in capillary permeability. In rat venules stimulated with proinflammatory substances ex vivo, the GAG-containing proteoglycan, syndecan-1, is shed from the endothelium. We wanted to investigate if we could trace the same response during septic shock as reflected in the circulating GAG levels. Arterial plasma samples were collected from 18 consecutive septic shock patients admitted to our intensive care unit. Plasma GAGs were measured with an Alcian blue slot binding assay, and syndecan-1 levels were measured with enzyme-linked immunosorbent assay. Effects of GAGs on the antibacterial activity of plasma were assessed by a radial diffusion assay. The median plasma GAG level was significantly higher in the septic shock patients than in matched controls (median [interquartile range], 2.7 μg/mL [1.9 - 4.8 μg/mL] vs. 1.8 μg/mL [1.7 - 2.0 μg/mL]). Furthermore, the GAG levels were significantly higher in nonsurvivors (4.6 μg/mL [3.1 - 8.8 μg/mL], n = 8) than survivors (1.8 μg/mL [1.6 - 2.6 μg/mL], n = 10). The syndecan-1 levels were also increased in the patients compared with controls (246 ng/mL [180 - 496 ng/mL] vs. 26 ng/mL [23 - 31 ng/mL]) and correlated to the cardiovascular Sequential Organ Failure Assessment (SOFA) score. The GAGs inhibited the endogenous antibacterial activity of plasma as well as isolated antimicrobial peptides. The concentrations required were in the same range as the GAG levels measured in the patients. These results show that the GAG levels are increased in septic shock patients, possibly reflecting peripheral endothelial cell damage. We also found that GAGs in relevant concentrations neutralize antimicrobial peptides in plasma.