Sepsis is still a leading cause of death on intensive care units. Despite intensive research, only few new therapies have been developed and used in the clinical setting. The fibrin fragment Bβ15-42 was already shown to preserve endothelial barrier function by binding to VE-cadherin and thus stabilize the interendothelial junctions. This was accompanied by reduced inflammation. Now we show that treatment with Bβ15-42 reduces inflammation in a murine polymicrobial sepsis model. Administration of Bβ15-42 reduced proinflammatory cytokine levels in the lung, liver, and blood and decreased neutrophil infiltration into the lung. Analysis alanine aminotransferase and aspartate aminotransferase further indicated reduced liver damage following polymicrobial sepsis. In vitro experiments using endothelial cells and macrophages further revealed that Bβ15-42 had no direct effect on Toll-like receptor-mediated inflammation. Therefore, we assume that attenuated inflammation is rather due to sustained vascular integrity and thus suppresses vascular leakage and subsequently leukocyte infiltration during sepsis.