ABSTRACT— The present study was undertaken in order to elucidate the effect of liver injury exerted by the antimicrotubular drug griseofulvin on hepatic transglutaminase activity in mice. Griseofulvin treatment of mice leads to a significant increase of transglutaminase activity associated with the 105 000 x g supernatant of liver homogenate, which is readily reversible after replacement of the griseofulvin-containing diet by a normal diet. Neoplastic nodules originally induced by prolonged griseofulvin feeding also show increased transglutaminase activity in contrast to reports in the literature. The increase in hepatic transglutaminase activity in griseofulvin-fed mice could be due either to mitotic inhibition exerted by the drug or to disturbance of intracellular Ca++ homeostasis following membrane injury. The second possibility could also account for the increased enzyme activity in neoplastic nodules. Similar events have been described as occurring in aging erythrocytes and terminally differentiating keratinocytes. The pathologic consequences and the substrates of increased hepatic transglutaminase activity have still to be elucidated.