Metabolic effects of in vivo administration of nitromethane, a histidase inhibitor, were studied in the rat. Histidinemia produced by feeding a 5-percent histidine diet to the rat was included for comparison. Rats injected subcutaneously with nitromethane every other day appeared to be histidinemic, with a plasma histidine level of 43 µmol/100 ml (control 9.2 µmol/100 ml) after 12 days of treatment. Histidine concentrations in the brain, liver, kidney, and urine of the nitromethane-treated rats were also increased. Liver histidase activity was decreased about 75 % after nitromethane administration, and the rate of in vivo CO₂ production from histidine was also depressed. No abnormal change in liver and kidney sizes was observed in these animals. Rats fed the 5-percent histidine diet showed markedly higher plasma histidine concentrations (99 µmol/100 ml) than the nitromethane-treated rats. The magnitude of increase in plasma histidine in the histidine-fed rats was considerably greater than that observed in humans with histidinemia. Furthermore, the liver histidase activity was decreased only by about 20 %, and a significant increase in liver and kidney sizes was noted in the histidine-fed animals. These findings indicate that histidinemia produced by nitromethane administration is a better model for studies of the genetic disorder than histidinemia induced by high levels of histidine in the diet.