To evaluate whether Mallory bodies (MBs) are linked to the induction of the enzyme γ-glutamyl transferase (GGT), mice were fed 2.5% griseofulvin (GF). The experimental and control mice livers were examined at four time periods, i.e., after 4 months' of GF feeding, 1 month after GF withdrawal and 13 days after GF refeeding, and at sacrifice after 4 months of GF withdrawal. The livers from mice continuously fed GF or control diet for 10 months were also examined. Tumors and nontumorous livers were examined histologically, histochemically, electron microscopically, and immunocytochemically. The tumors consisted of hepatomas and hyperplastic nodules. To localize MBs inside GGT-positive cells, a double-staining method was employed; GGT-positive cells were identified histochemically followed by staining for MBs using the unlabeled immunoperoxidase technique. The per cent area of the GGT-positive foci was closely correlated with the frequency of MBs observed in the course of a GF feeding and withdrawal. Almost all of the MBs were located in GGT-positive cells in both tumors and nontumor liver tissue. MBs and GGT positivity involved the same liver cells. They both were found in high frequency in tumors induced by GF. These results indicate that MB formation, like GGT induction, is a phenotypic change induced by GF. The coexistence of the two phenomenon in the same cell throughout all phases of tumor formation suggests that MBs may be related to the neoplastic process in the GF-fed mouse model.