Objective:To determine the mechanism for the reduced polymorphonuclear neutrophil exudation to secondary inflammatory sites in critically ill patients with infection and systemic inflammatory response (sepsis).Design:Prospective cohort study.Setting:Research laboratory and integrated intensive care unit of a tertiary care university-affiliated teaching hospital.Patients:Healthy subjects or critically ill patients with confirmed infection and a systemic inflammatory response (septic patients).Measurements and Main Results:We found that polymorphonuclear neutrophil delivery to a secondary inflammatory site (skin window blisters) is reduced by >70% in humans with sepsis, defined as serious infection and a systemic inflammatory response compared with healthy controls. The expression of the endothelial adhesion molecules intercellular adhesion molecule-1, E-selectin and P-selectin in microvessels from skin biopsies was comparable in the two study groups. Also, CD11a and CD11b levels were equal in circulating polymorphonuclear neutrophils (PMNs) from both study groups. Both adhesion molecules were markedly and equally up-regulated during exudation. Circulating PMNs from septic patients showed marked shedding of L-selectin compared to those of healthy controls, with a corresponding increase in their plasma L-selectin levels. An increased concentration gradient between plasma and exudate fluid was found for tumor necrosis factor-α and interleukin-8 in septic patients, but not for C5a. The phagocytic and bactericidal capacity of septic patient circulating PMNs was higher then in healthy control patients, but these differences were lost after exudation. There were no major differences in oxidative burst or intracellular calcium flux of circulating PMNs from the two study groups. Polymorphonuclear neutrophil exudation primed both responses to different extents.Conclusions:Septic patients deliver fewer PMNs to secondary inflammatory sites. In addition, neutrophil exudation results in loss of the small priming effect for phagocytosis and bactericidal function induced by sepsis. Failure to produce a gradient to C5a and intravascular shedding of L-selectin may be responsible for this sepsis-induced reduction in neutrophil exudation to secondary inflammatory sites.