Necrosis and apoptosis are distinct, but nonexclusive mechanisms of cell death. Until recently, investigators have focused upon necrosis as the sine qua non of lethal cell injury. Specifically, within the realm of liver transplantation, preservation strategies dealing with ischemia/reperfusion injury have concentrated upon minimizing the biochemical and histologic correlates associated with necrosis. Little is known of the role of apoptosis in reperfusion injury in human liver transplantation. Post-reperfusion liver biopsies from 35 patients were retrospectively analyzed for histologic evidence of necrosis. Apoptosis was identified histologically and using a chromogenic technique of in situ labeling of fragmented DNA. The number of apoptotic cells increased in parallel with the necrosis reperfusion score in a significant fashion (p = 0.003 by ANOVA). There was not a Zone 1, 2 or 3 predominance to the histologic distribution of apoptotic cells. The recipient peak serum transaminase values were also noted to increase with the reperfusion score (p = 0.001 by ANOVA). These results suggest that: 1) apoptosis occurs in the setting of reperfusion injury during human orthotopic liver transplantation (OLT); and 2) the extent of apoptosis increases in parallel with pathologic and biochemical parameters of reperfusion injury. Given the distinct nature of apoptosis and the highly regulated and conserved pathway for its initiation, inhibition of apoptosis with specific molecular targets, may serve to decrease allograft reperfusion injury.