Prophylactic use of anticoagulants during sepsis is strongly recommended for the prevention of venous thrombosis. Moreover, recent studies suggested the positive effects of anticoagulants to the inflammation. In this study, we planned to confirm the effects of heparins on protecting against endothelial damage in endotoxemia. In addition, we also examined the differences between unfractionated heparin (UFH) and enoxaparin. Wistar rats received 8.5 mg/kg (i.v.) LPS, followed by a bolus infusion of either 350 U/kg of UFH, 2.0 mg/kg of enoxaparin, or placebo. Microscopic observation of the mesenteric microcirculation and the measurement of the bleeding area after puncture with a microneedle were performed 3 h later (n = 6 in each group). In another series, blood samples were taken 3 h after the LPS injection, and blood cell counts, coagulation markers, and organ damage markers were measured (n = 6 in each). As a result, the leukocyte adherence to the endothelium was significantly reduced in both the UFH and enoxaparin groups, and thus, endothelial damage was attenuated in these groups. The bleeding area was markedly expanded in the UFH group compared with the other groups (P < 0.01 each). The decrease in white blood cells and platelet count was significantly suppressed in the enoxaparin group compared with the UFH group (P < 0.05 each). The fibrinogen level was maintained at significantly better levels, and the elevation of alanine aminotransferase was significantly suppressed in enoxaparin group (P < 0.05 each). In conclusion, both UFH and enoxaparin protect against endothelial damage by preventing leukocyte adhesion. However, UFH significantly increases the bleeding area, whereas enoxaparin does not increase bleeding, and thus, it can reduce organ damages in the endotoxemic rat.