We studied the effects of putrescine on acute liver failure caused in rats by two injections of 1 gm/kg D-galactosamine. The hepatic polyamine level rose only slightly in the D-galactosamine–injected rats treated with glucagon and insulin, and [3H]thymidine incorporation into DNA increased little; these hormones did not improve the survival rate. When D-galactosamine–injected rats were given putrescine, the putrescine concentration in the liver increased and the survival rate of the rats was significantly higher than that of control rats given only D-galactosamine. Putrescine administration tended to lower the serum level of alanine aminotransferase in rats injected with D-galactosamine, so the polyamine might have a protective effect on hepatocytes. Putrescine significantly increased [3H]thymidine incorporation in the liver; thus it accelerated liver regeneration. Difluoromethylornithine decreased the level of putrescine in the liver, decreasing both [3H]thymidine uptake and the survival rate. In the rats treated with D-galactosamine, in which liver damage was so severe that treatment with glucagon and insulin was ineffective, the intraperitoneal administration of putrescine increased the survival rate in acute liver failure. This probably resulted mainly from activation of liver regeneration and possibly from a protective effect of putrescine on the liver. (HEPATOLOGY 1990;12:348–353).