Extravasation of leukocytes at sites of ischemia may mediate tissue injury. To determine how leukocyte accumulation may be induced by ischemia, effects of hypoxia on basal neutrophil expression of adhesion and activation receptors were examined. Effects of hypoxia upon preactivated cells were also studied. To determine whether regulation of expression is dependent on oxygen availability or on mitochondrial respiration, the effects of physical hypoxia (substitution of O₂ by nitrogen) were compared with those of chemical hypoxia with sodium cyanide (NaCN). Leukocytes in whole blood (eight volunteers) were exposed either to hypoxia alone or to priming concentrations of lipopolysaccharide (LPS, 1 μg/ml) followed by chemical hypoxia (NaCN, 1 mM) or physical hypoxia (PO₂ of 1-10 torr) for various time intervals. Room air was controlled and hypoxic cells were labeled with fluorescent monoclonal antibodies to integrins CD18 and CD11b or to the 55kDa TNFα cell surface receptor (TNFR). Receptor concentrations were measured by flow cytometry. Data were analyzed by ANOVA/Student's t test. Physical hypoxia increased expression of both CD11b and CD18 over time and augmented their LPS-induced up-regulation. Isolated chemical hypoxia did not change neutrophil expression of CD11b or CD18, but partially inhibited neutrophil CD11b and CD18 up-regulation by LPS. LPS-induced TNFR down-regulation was not affected by physical hypoxia, which failed to alter TNFR expression in this model. Chemical hypoxia led to an up-regulation of TNFR in neutrophils, which was opposed by LPS. Physical hypoxia exerts a specific effect on expression of leukocyte receptors, which is substantially different from that exerted by chemical hypoxia.