The enhanced repair of O6-methylguanine from hepatic DNA in rats is a well established phenomenon that can be induced by pretreatment with a variety of hepatotoxic agents as well as by partial hepatectomy. Attempts to induce a similar hepatic response by treatment with single doses of aflatoxin B1 in C57Bl mice, single doses of dimethylnitrosamine (DMN) in C57Bl or BALB/C mice or by prolonged pretreatment with DMN by addition to the drinking water of C57Bl mice were uniformly unsuccessful. Furthermore, the intense proliferative response induced by two-thirds partial hepatectomy in C57Bl mice was also apparently incapable of increasing the activity of this repair function. These experiments, in which repair of O6-methylguanine has been determined both in vivo after administration of [14C]DMN and in vitro using crude tissue extracts and a methylated DNA substrate, indicate the presence of an intergeneric difference between rats and mice with respect to this repair function.