BACKGROUND The goal of this study was to observe the effect of the apoptosis of Kupffer cells (KCs) selectively induced by zoledronate liposomes following the hepatic ischemia-reperfusion injury (IRI) in the rat liver transplantation model and to explore its mechanisms. MATERIAL AND METHODS The rat liver transplantation model was established using the improved Kamada method. Male Sprague Dawley rats were randomly divided into 3 groups: no liver transplantation or drug treatment (Group A); donor rats were injected with 1 mL normal saline through the tail vein for 3 continuous days before transplantation, and the donor liver was preserved in cold for 2 hours (Group B); donor rats were injected with 1 mL zoledronate liposomes (0.001 mg/mL) through the tail vein for 3 continuous days before transplantation, and the donor liver was preserved in cold for 2 hours (Group C). At 24 hours after transplantation, the receiving rats were sacrificed for sampling. RESULTS Compared with Group C and Group A, the bile secretion flow was dramatically decreased in Group B, whereas the serum liver function index [alanine aminotransferase (ALT), glutamate aminotransferase (AST), and γ-glutamyl transpeptidase (γ-GT)] was significantly increased (P<0.01), and the pathological injury area was obviously increased. Compared with Group B, the levels of serum interleukin1 (IL-1), tumor necrosis factor-α (TNF-α), and the apoptotic index in Group C were significantly decreased (P<0.05), and Suzuki scores of congestion, vacuolar degeneration, and necrosis were all reduced (P<0.05). CONCLUSIONS The apoptosis of KCs selectively induced by zoledronate liposomes inhibited the inflammatory cascade reaction induced by KC activation and reduced the release of cytokines and decreased the extent of IRI in the liver transplantation in animal model.