The malcirculation caused by the vascular endothelial injury plays the important roles in the development of septic organ dysfunction. The natural anticoagulant, activated protein C (APC) is expected not only to regulate the hypercoagulability but also to modulate the leukocyte-endothelial interaction. [Purpose] The aim of this study is to examine the effects of APC on pro-inflammatory cytokine production and leukocyte-endothelial interaction in endotoxemia. [Methods] Rats were injected either 100, 000 U·kg^-1 of plasma derived APC (APC group, n=12) or 0.5% human albumin (control group, n=12), 30min prior to 2.5 mg·kg^-1 of endotoxin (LPS) injection. Plasma levels of tumor necrosis factor (TNF), interleukin-6 (IL-6), cytokine-induced neutrophil chemoattractant (CINC) and monocyte chemoattractant protein-1 (MCP-1) were measured at 1 and 3hr after LPS injection (n=5 in each group). In another series, the frequency of leukocyte rolling and sticking were measured at 1, 2 and 3hr after LPS injection under the intravital microscope (n=7 in each group). [Results] APC suppressed the elevated levels of TNF at 1 and 3hr (P<0.01, respectively) and IL-6 at 3hr (P<0.05) after LPS injection. CINC level was significantly suppressed at 3hr after LPS injection in APC group (P<0.05). On the other hand, MCP-1 level was not affected by APC. Significant decreases in leukocyte rolling and sticking were observed in APC group. In summary, APC suppresses the production of inflammatory cytokines such as TNF, IL-6 and CINC, and inhibits the leukocyte-endothelial interaction. These changes lead to the improvement of microcirculation during endotoxemia.