Mild to moderate liver injury to the orthotopically transplanted liver may result from acute rejection, mild ischaemia, or viral hepatitis. Because these conditions are often clinically indistinguishable, liver biopsy is frequently helpful. We previously characterized and reported the morphological spectrum of mild-to-moderate ischaemic injury from 170 liver biopsies (51 liver transplant patients). During this review, we found eight patients with a diffuse hepatocyte ballooning pattern. This pattern had some similarity to 'preservation injury' described by others, and in fact seven of the eight patients had these changes within the first 2 weeks post-transplant. However, two of the seven patients also displayed these changes up to 6 months post-transplant and the eight patient developed these histological patterns only after the early post-transplant period. Follow-up data on patients with diffuse hepatocyte ballooning showed that some reverted to normal histology, some transformed to well-delineated perivenular ballooning, and some progressed to perivenular necrosis and/or infarction. Only when superimposed perivenular necrosis became apparent did the injury become irreversible, necessitating allograft removal or resulting in death. The pathogenesis of diffuse hepatocyte ballooning is unclear. However, the association of some of the cases with 'preservation injury' pattern in the early post-transplant period and the progression of others to necrosis and infarction, suggest an ischaemic basis for this lesion.