Activation of the complement cascade represents an important event during ischemia/reperfusion injury (IRI). This work was designed to investigate the role of the membrane attack complex (MAC; C5b-9) in the pathogenesis of hepatic IRI. Livers from B&W/Stahl/rC6(ϩ) and C6(Ϫ) rats were harvested, stored for 24 hours at 4°C, and then transplanted [orthotopic liver transplantation (OLT)] to syngeneic recipients. There were 4 experimental groups: (1) C6(ϩ)3 C6(ϩ), (2) C6(ϩ)3 C6(Ϫ), (3) C6(Ϫ)3 C6(ϩ), and (4) C6(Ϫ)3 C6(Ϫ). At day ϩ1, C6(Ϫ) OLTs showed decreased vascular congestion/necrosis, contrasting with extensive necrosis in C6(ϩ) livers, that was independent of the recipient C6 status (Suzuki score: 7.2 Ϯ 0.9, 7.3 Ϯ 1.3, 4.5 Ϯ 0.6, and 4.8 Ϯ 0.4 for groups 1-4, respectively, P Ͻ 0.05). The liver function improved in recipients of C6(Ϫ) grafts (serum glutamic oxaloacetic transaminase: 2573 Ϯ 488, 1808 Ϯ 302, 1170 Ϯ 111, and 1188 Ϯ 184 in groups 1-4, respectively, P Ͻ 0.05). Intragraft macrophage infiltration (ED-1 immunostaining) and neutrophil infiltration (myeloperoxidase activity) were reduced in C6(Ϫ) grafts versus C6(ϩ) grafts (P ϭ 0.001); these data were confirmed by esterase staining (naphthol). The expression of proinflammatory interferon-␥, interleukin-1, and tumor necrosis factor messenger RNA/protein was also reduced in C6(Ϫ) OLTs in comparison with C6(ϩ) OLTs. Western blot-assisted expression of proapoptotic caspase-3 was decreased in C6(Ϫ) OLTs versus C6(ϩ) OLTs (P ϭ 0.006), whereas antiapoptotic Bcl-2/Bag-1 was enhanced in C6(Ϫ) OLTs compared with C6(ϩ) OLTs (P ϭ 0.001). Terminal deoxynucleotidyl transferase-mediated dUTP nick end-labeling staining of apoptotic cells was enhanced (P Ͻ 0.05) in C6(ϩ) OLTs compared with C6(Ϫ) OLTs. Thus, the terminal products of the complement system are essential in the mechanism of hepatic IRI. This is the first report using a clinically relevant liver cold ischemia model to show that local MAC inhibition attenuates IRI cascade in OLT recipients.