Platelets drive liver injury in murine models of viral hepatitis(1) and promote liver regeneration through the release of serotonin(2). Despite their emerging role in inflammatory liver disease little is known about the mechanisms by which platelets bind to the hepatic vasculature. We used human explanted tissue specimens and peripheral blood to investigate the mechanisms and consequences of platelet binding. Human hepatic sinusoidal endothelial cell (HSEC) adhesion receptor expression was determined by analysis of public SAGE expression data. We then used a combination of modified Stamper Woodruff adhesion assays and flow-based endothelial adhesion assays with cultured HSEC and human platelets and leucocyte populations, along with histochemical analysis of human explanted liver specimens and NF-KB activity assays. 1,5353 genes with differentially expressed in HSEC (FDR q-value <=0.05 with posterior probability of >= 0.8) compared to endothelium from kidney, breast, lung and aorta and of these 864 were enriched in HSEC. Expression of sinusoidal endothelial phenotypic indicators(3) CD32b (FCGR2B), LYVE-1, CLEVER-1 (STAB1) and mannose receptor was increased in HSEC, which had reduced expression of VWF, αv integrin and CD31. Exogenous platelets bound avidly to hepatic vessels in normal and chronically injured human liver tissue, and became activated on the diseased tissue. Adhesion was integrin dependent (>60% decrease 100ug/ml RGD peptide, p<0.001, n=3 livers) inhibited by blocking platelet CD41, and supported by binding to immobilised fibrinogen on the tissue endothelium (>50% decrease 100ug/ml Fb-binding peptide, P<0.05, n=3 livers). Flow based adhesion assays confirmed that binding of platelets to HSEC under flow was significantly inhibited by antibody raised against Gp1b (29±18% of control), Fb-peptide(53.5±20%),αIIb integrin(36.7±7.2%) and αv integrin(36.2±4.7%, P<0.05 for all, n=4 HSEC isolates). Binding of platelets resulted in activation of endothelial NF-KB, and a significant increase in secretion of CXCL8 (2600±300pg/ml vs 300±290pg/ml control, n=3 HSEC isolates p<0.001) and CCL2 (900±150pg/ml vs 260±175pg/ml control) by HSEC. Importantly platelet attachment to HSEC increased binding of neutrophils and lymphocytes under flow, and adhesion was inhibited using a P-Selectin inhibitor. In conclusion, we have demonstrated that resting platelets can adhere to human HSEC using the integrins αIIbβ3 and αVβ3 under physiological shear stress. Our findings explain how platelets bind to hepatic vessels and suggest that such interactions promotes immune cell recruitment by triggering chemokine secretion and providing an adhesive substrate for circulating leukocytes.