The status of the excitatory glutamatergic neurotransmitter system in hepatic encephalopathy has been studied. Synaptic membranes (SM) were prepared from the brains of normal rabbits, hyperammonemic normal rabbits, and rabbits with fulminant hepatic failure. Data on the specific binding of glutamate to SM indicated that fulminant hepatic failure was associated with a decrease in the number of glutamate receptors on SM from cerebral cortex, cerebellum, and particularly the hippocampus, without any associated change in the affinity of these receptors. In contrast, hyperammonemia was associated with an increase in the affinity and no decrease in the number of glutamate receptors on SM from the hippocampus. These findings indicate that the effects of hyperammonemia and fulminant hepatic failure on cerebral glutamate receptors are fundamentally different. The decreased number of glutamate receptors in hepatic encephalopathy might reflect a decreased sensitivity of glutamatergic neurons to glutamate-mediated neural excitation, a phenomenon that could contribute to the neural inhibition of hepatic encephalopathy.