The histopathological features of orthotopic liver transplants were evaluated in 63 serial biopsy specimens from 17 patients. Biopsies were taken at the time of insertion of the liver (six biopsies), at the time of development of liver function abnormalities (11 biopsies) and as follow-up to previously abnormal biopsies (46 biopsies). The biopsies taken at the time of insertion all showed diffuse hepatocellular ballooning with confluent areas of necrosis in one case. Biopsies taken at the time of onset of rejection (nine cases) all showed a mixed portal inflammatory infiltrate, bile duct damage and central or portal vein endothelialitis (i.e., attachment of lymphocytes to the vein endothelium). Follow-up biopsies showed several patterns including: (i) resolution of changes of acute rejection with subsequent development of recurrent acute or chronic rejection (four cases); (ii) prolonged acute rejection simulating extrahepatic biliary obstruction (four cases); (iii) prolonged acute rejection with predominance of eosinophils simulating a drug reaction (one case); and (iv) rapidly progressive acute rejection leading to death (one case). Biopsy of the transplanted liver at the time of transplantation is useful to provide a baseline for comparison with later biopsies. Biopsy at the time of onset of changes in liver function is essential to confirm the presence of rejection prior to alteration of immunosuppression.