Early vascular occlusion is liable to cause graft failure, and differential diagnosis between this condition and primary nonfunction (PNF) caused by preservation injury may be difficult. Apoptosis has been detected in immunomediated cytotoxicity and is known to be triggered by mild ischemia. In a retrospective analysis we investigated the role of apoptosis in vascular occlusion, PNF, and acute allograft rejection to improve the differential diagnosis of early graft failure. The liver graft histology of 75 patients (46 male, 29 female) a median 47 (1-64) years of age was screened semiquantitatively for the rate of apoptosis on the hematoxylin-eosin stain (HE) and by the in situ end nick labeling technique (TUNEL). This cohort included all patients who developed PNF (n = 9) or vascular occlusion (n = 11) after orthotopic liver transplantation (OLT) in the years 1992 to 1996. Within this period of time we performed 205 OLTs on 189 patients. We further included 22 patients with early acute rejection and 11 controls. The highest rates of apoptotic hepatocytes were seen in vascular occlusion (P < 0.001). Grafts with PNF were explanted 1-3 days after OLT and showed hepatocytes that were 100% necrotic. Cases of acute early rejection showed a significantly higher apoptotic cell count than did normal controls (P < 0.003), increasing in direct proportion to the severity of rejection. Screening biopsies for the rate of apoptosis can improve the efficacy and accuracy of differential diagnosis of early graft failure.