Background.We hypothesized that systemic release of endogenous leukocyte-derived polypeptide antimicrobial defensins (polymorphonuclear leukocyte-specific) and lactoferrin (polymorphonuclear leukocyte and epithelial cell derived) occurs in nonneutropenic children with severe sepsis.Methods.We performed a prospective cross-sectional and longitudinal study in a university children’s hospital pediatric intensive care unit. Ninety-two consecutive children meeting criteria for sepsis and 14 critically ill children without sepsis (controls) were enrolled, and plasma defensins and lactoferrin concentrations were measured on Days 1 and 3 of sepsis.Results.Nonneutropenic sepsis patients (n= 71) had increased defensins and lactoferrin plasma concentrations compared with critically ill control patients [defensins, 450 ng/mlvs.150 ng/ml; lactoferrin, 332 ng/mlvs.176 ng/ml (median values);P< 0.05] and neutropenic sepsis patients [n= 21; defensins, 450 ng/mlvs.50 ng/ml; lactoferrin, 332 ng/mlvs.20 ng/ml (median values);P< 0.05]. Neutropenic sepsis patients had similar plasma defensin concentrations and a decrease in plasma lactoferrin concentrations compared with control patients (P< 0.05). Defensins and lactoferrin plasma concentrations correlated to total white blood cell and absolute neutrophil count (P< 0.05). There was no association between plasma defensin concentration and organ failure or outcome; however, increased plasma lactoferrin concentrations were observed with the development of organ failure (P< 0.05).Conclusion.These data suggest that increased circulating defensins and lactoferrin release are dependent in part on neutrophil count and might play a role in host defense in children with severe sepsis.