Endocan is a proteoglycan secreted by endothelial cells under the control of inflammatory cytokines. The aim of this study was to evaluate the effects of endocan on proinflammatory responses and on septic mice and underlying mechanisms. Human umbilical vein endothelial cells (HUVECs) or mice were exposed to lipopolysaccharide (LPS) or endocan with or without neutralizing endocan antibody. Mice were subjected to cecal ligation and puncture (CLP) surgery with or without neutralizing endocan antibody. Endocan was highly released by LPS and it enhanced proinflammatory responses. In a CLP‐induced sepsis model, endocan was also highly released, but this release was prevented by administration of neutralizing endocan antibody. Circulating levels of endocan measured in patients admitted to the intensive care unit with sepsis were significantly elevated compared with control donors. Furthermore, the administration of endocan antibody reduced CLP‐induced sepsis mortality. This study shows endocan can elicit severe inflammatory responses and inhibiting endocan release offers a potential strategy for treating sepsis. J. Cell. Physiol. 229: 620–630, 2014. © 2013 Wiley Periodicals, Inc.