Rationale: Myeloid related protein (MRP) 8 and 14 can form heterodimers that elicit a variety of inflammatory responses. We recently showed that MRP8/14 is a ligand for Toll-like receptor 4, and that mice deficient in MRP8/14 are protected against endotoxic shock-induced lethality. Objectives: To determine 1) the extent of MRP8/14 release in patients with sepsis and/or peritonitis and in healthy humans exposed to lipopolysaccharide (LPS) and 2) the contribution of MRP(8/)14 to the host response in murine abdominal sepsis. Methods: MRP8/14 was measured in 51 severe sepsis patients, 8 subjects after intravenous injection with LPS and 17 patients with peritonitis. Host responses to sepsis were compared in mrp14 gene deficient (and thereby MRP8/14 deficient) and wild-type mice intraperitoneally injected with Escherichia (E.) coli. Measurements and Main Results: Sepsis patients displayed elevated circulating MRP8/14 concentrations at both days 0 and 3, and LPS injection resulted in systemic MRP8/14 release in healthy humans. In patients with peritonitis, MRP8/14 levels in abdominal fluid were >15-fold higher than in plasma. MRP14 deficient mice displayed an improved defense against E. coli abdominal sepsis in an early phase, as indicated by a diminished dissemination of the bacteria at 6 h. In addition, MRP14 deficient mice demonstrated decreased systemic inflammation, as reflected by lower cytokine plasma concentrations, and less severe liver damage. Conclusion: Human sepsis and endotoxemia are associated with enhanced release of MRP8/14. In abdominal sepsis, MRP8/14 likely primarily occurs at the site of the infection, facilitating bacterial dissemination in an early phase and liver injury.