Background. The chemokine fractalkine (CX3CL1) is critically involved in the pathophysiology of different inflammatory diseases and myocardial ischemia-reperfusion (I/R). This study aims to analyze the role of fractalkine in the activation of platelets and leukocytes during hepatic I/R. Methods. Under inhalation anesthesia, C57BL6 mice were subjected to warm hepatic I/R (90min/240min). The animals were pretreated either with a function-blocking anti-mouse CX3CL1 antibody or IgG control administered systemically before ischemia. Sham-operated animals served as controls (n=7 each group). The inflammatory response and sinusoidal perfusion failure were evaluated by intravital microscopy. Hepatic transaminases plasma levels and histopathological tissue damage were determined as markers of hepatocellular injury. Results. Sinusoidal perfusion failure, leukocyte recruitment to the liver, and transaminase activities were sharply increased upon I/R compared to sham-operated mice. Firm adhesion of platelets and concordantly leukocytes to endothelial cells is reduced significantly by a function-blocking anti-fractalkine antibody. We demonstrate that inhibition of fractalkine signaling attenuates leukocyte adhesion in the postischemic liver but does not significantly ameliorate overall perfusion failure and hepatocellular injury. Discussion/Conclusion. Our in vivo data demonstrate a mild attenuating effect of CX3CL1 blockade on platelet and leukocyte, but not CD4+ T cell accumulation and activation in hepatic I/R injury. We report a significant effect of blocking chemokine fractalkine on sinusoidal perfusion failure without considerably improving overall hepatocellular injury during early reperfusion.