Sepsis is associated with an activation of the coagulation system and multi-organ failure. The aim of the study was to examine the effects of selective thrombin inhibition with melagatran on renal hemodynamics and function, and liver integrity, during early endotoxemia. Endotoxemia was induced in thiobutabarbital anesthetized rats by an intravenous (i.v.) bolus dose of lipopolysaccharide (LPS; 6 mg/kg). Study groups (1) Sham-Saline, (2) LPS-Saline and (3) LPS-Melagatran, received isotonic saline, or melagatran, immediately before (0.75 µmol/kg i.v.) and continuously during 4.5 h of endotoxemia (0.75 µmol/kg/h i.v.). Kidney function, renal blood flow (RBF), and intrarenal cortical and outer medullary perfusion (OMLDF) measured by laser-Doppler flowmetry, were analyzed throughout. Markers of liver injury and tumor necrosis factor (TNF)- were measured in plasma after 4.5 h of endotoxemia. In addition, liver histology and gene expression were examined. Melagatran treatment prevented the decline in OMLDF observed in group LPS-Saline (p<0.05, LPS-Melagatran vs. LPS-Saline). However, melagatran did not ameliorate reductions in mean arterial pressure, RBF, renal cortical perfusion and glomerular filtration rate, or attenuate tubular dysfunctions, during endotoxemia. Melagatran reduced the elevated plasma concentrations of aspartate aminotransferase (-34±11 %, p<0.05), alanine aminotransferase (-21±7 %, p<0.05), bilirubin (-44±9 %, p<0.05) and TNF- (-32±14 %, p<0.05) in endotoxemia. Melagatran did not diminish histological abnormalities in the liver, or the elevated hepatic gene expression of TNF-, intercellular adhesion molecule-1, and inducible nitric oxide synthase, in endotoxemic rats. In summary, thrombin inhibition with melagatran preserved renal OMLDF, attenuated liver dysfunction and reduced plasma TNF- levels, during early endotoxemia.