Although it is becoming increasingly common to accept livers from older donors for transplantation, old livers are more damaged by hepatic ischemia and reperfusion injury (HIRI) than young livers. We hypothesized that this age-related susceptibility to HIRI is due to increased hepatocellular apoptosis driven by tumor necrosis factor α (TNFα). Young (6-week-old) and old (60-week-old) mice underwent 60 minutes of hepatic ischemia and increasing periods of reperfusion. TNFα was determined by enzyme-linked immunosorbent assay. Liver injury (enzyme release), apoptosis (terminal deoxynucleotidyl transferase–mediated deoxyuridine triphosphate–digoxigenin nick-end labeling staining, cytochrome C release, and caspase activation), and necrosis (hematoxylin and eosin staining) were assessed. We assessed the impact of apoptosis by blocking TNFα production or effect (pentoxifylline and TNFα receptor knockout), inhibiting apoptotic pathways (caspase inhibition), or imposing a hepatic protective strategy [glucose infusion with ischemic preconditioning (Glc/PC)]. In comparison with young livers, old livers subjected to HIRI had more pronounced liver aspartate aminotransferase release (6200 versus 3900 U/L, P = 0.02), necrosis (45% versus 25%, P = 0.03), and apoptosis with increased 30-minute TNFα release (19.02 versus 10.62 pg/mg, P = 0.03). Eliminating TNFα production reversed the effect of age, as did inhibition of apoptotic pathways with caspase inhibition. Glc/PC of old mice attenuated TNFα release (9.56 versus 19.02 pg/mg, P = 0.001) and age-related exaggerated HIRI and improved survival (60% versus 0%). In conclusion, the age-related susceptibility to HIRI is driven by an exaggerated induction of TNFα-dependent hepatocellular apoptosis. Targeting the apoptotic cascade has implications for the older donor liver population. Liver Transpl 15:1594–1604, 2009. © 2009 AASLD.