To test the association of small bile duct destructive lesions in the liver with acute graft-versus-host disease, a blind (coded) histological study was done comparing liver tissue from three groups of dogs given 1,200 R of total-body irradiation: one not given marrow infusions after irradiation, another given autologous hemopoietic grafts, and a third given marrow grafts from DLA-nonidentical unrelated donors. The dogs with unrelated grafts all developed graft-versus-host disease, and their liver histology was distinguished from that of the dogs in the other two groups by three findings: (1) extensive small bile ductule necrosis and atypia; (2) infiltrates of mononuclear cells around and in ductules; and (3) individual hepatocyte necrosis scattered throughout the lobules. Thus, bile duct lesions appear to be a good marker for assessing the presence and severity of hepatic graft-versus-host disease in dogs.