It has been proposed that abnormal mechanical properties may contribute to capillary retention of polymorphonuclear leukocytes (PMN) in sepsis, leading to the development of organ dysfunction. The present study was designed to determine whether PMN rigidity is increased in severe sepsis, and whether changes in the rheologic behavior of PMN correlate with the clinical course in sepsis. Eighteen adults with severe sepsis were studied over a period of 14 d; 11 survived and seven died. PMN deformation behavior was investigated via micropore filtration, using the cell transit analyzer. On Day 0, PMN rigidity was 2.5-fold greater for sepsis patients than for five normal controls (p < 0.001). PMN rigidity progressively improved over the 14 d study period for patients who recovered, but not for those who died; clinical indicators correlated with PMN rigidity. Patient PMN also exhibited a 5-fold greater increase in rigidity in response to formyl-methionylleucylphenylalanine (fMLP) than did control PMN. Both the increased rigidity and enhanced response to fMLP could be simulated in vitro by incubation of normal PMN with tumor necrosis factor-alpha (TNF-alpha). We conclude that circulating PMN are more rigid in severe sepsis, and are "primed" for an augmented response to chemotactic stimuli. These findings support the hypothesis that cytokine-mediated increases of PMN rigidity may lead to sequestration of these cells in capillaries and to the consequent impairment of microvascular perfusion in sepsis.