Cytotoxic brain edema was produced in rabbits with intraperitoneal administration of a metabolic inhibitor, 6-aminonicotinamide. Paraplegia, diminished feeding, globally diminished muscle tone, and poor coordination were evident 48 hours after the initial administration of the drug and the electroencephalogram (EEG) was characterized by pronounced slowing and diminished voltage. Cisternal monitoring of intracranial pressure (at a pACO2 of 38 to 42 torr) revealed that it was significantly higher than in controls (p < 0.001). Measurements of phosphocreatine, lactate, and NADH did not differ from control values, but total nicotinamide adenine dinucleotide (NAD+/NADH) showed a significant decrease in the experimental group (p < 0.001). Water content of the gray matter was significantly higher in the experimental group when compared to that in controls (p < 0.001). Mannitol and furosemide produced a significant reduction in intracranial pressure (ICP) (p < 0.001) and lowered the water content of the gray matter (p < 0.001). Both agents improved the slow wave form of the EEG 20 minutes after their administration intravenously in 50% of the animals. Dexamethasone (1 mg/kg) was administered with 6-aminonicotinamide 2 days before the experimental day. In 50% of this group, the behavior and EEG were similar to those of normal rabbits, and on the experimental day ICP was slightly lower than that in untreated animals (p < 0.01). The decrease in water content of the gray matter in the steroid group was significantly less than that produced by mannitol and furosemide.