Monocytes infiltrate damaged liver tissue during noninfectious liver injury and often have dual roles, perpetuating inflammation and promoting resolution of inflammation and fibrosis. However, how monocyte subsets distribute and are differentially recruited in the liver remain unclear. In the current study, the subpopulations of infiltrating monocytes were examined following liver ischemia/reperfusion (I/R) injury in mice using flow cytometry. CD11b(+)Ly6C high (Ly6C(hi)) cells (inflammatory monocytes) and CD11b(+)Ly6C low cells (reparative monocytes) were recruited into the liver following I/R injury. Treatment with clodronate-loaded liposomes, which transiently deplete systemic macrophages, alleviated hepatic damage. Mice genetically deficient in C-C motif chemokine ligand 2 (CCL2), or its receptor C-C chemokine receptor 2 (CCR2), exhibited diminished hepatic damage compared with wild-type mice following I/R, by controlling intrahepatic inflammatory Ly6C(hi) monocyte accumulation. In addition, the CCR2 specific inhibitor RS504393 alleviated hepatic I/R injury. The results suggest that the CCR2/CCL2 axis an important role in monocyte infiltration and may represent a novel target for the treatment of liver I/R injury.