Sepsis is a multifactorial, and often fatal disorder, typically characterized by widespread inflammation and immune activation with resultant endothelial activation. In the present study, we postulated that the adipokine adiponectin serves as a critical modulator of survival and endothelial activation in sepsis. To this aim, we evaluated both loss-of-function (adiponectin gene-deficient mice) and subsequent gain-of-function (recombinant adiponectin reconstitution) strategies in two well-established inflammatory models, cecal ligation perforation (CLP) and thioglyocollate-induced peritonitis. Adipoq^-/- mice, subjected to CLP, exhibited a profound (~8 fold) reduction in survival compared to their wild-type Adipoq^+/+ littermates after 48 hours. Furthermore, compared to wild-type controls, thioglycollate challenge resulted in a markedly greater influx of peritoneal neutrophils in Adipoq^-/- mice accompanied by an excess production of key chemoattractant cytokines (IL-12p70, TNF, MCP-1 and IL-6) and upregulation of aortic endothelial adhesion molecule VCAM-1 and ICAM-1 expressions. Importantly, all of these effects were blunted by recombinant total adiponectin administration given three days prior to thioglycollate challenge. The protective effects of adiponectin were largely ascribed to higher order adiponectin oligomers, since administration of recombinant C39A trimeric adiponectin did not attenuate endothelial adhesion molecule expression in thioglycollate-challenged Adipoq^-/- mice. These data suggest a critical role of adiponectin as a modulator of survival and endothelial inflammation in experimental sepsis and suggest a potential mechanistic link between adiposity and increased sepsis.