The effect of fructose 1–6 diphosphate (FDP) on brain metabolism and brain function was investigated in hypoglycemic rabbits. The electroencephalogram and differences in oxygen content of arterial and cerebral venous blood were used as indicators for brain metabolic activity. Hypoglycemic coma was induced and maintained for 1 hour by insulin administration. At the onset of isoelectric EEG, six rabbits were treated with FDP and five rabbits received 0.9% saline. The animals were killed by an overdose of barbiturate 60 minutes after hypoglycemic recovery with glucose, FDP-treated rabbits had lower arterial glucose concentration after 40 minutes of treatment (p < .05) and a significantly greater differences between the oxygen content of arterial and venous blood after 40 minutes (p < .01), and after 60 minutes (p < 0.025) of FDP infusion than saline-treated rabbits. FDP-treated rabbits also has a lower cerebral glucose-oxygen index than did saline-treated rabbits (p < .005), after 20 and 40 minutes of FDP infusion). FDP administration was followed by a return of EEG activity during hypoglycemia, whereas saline produced no such effect. After glucose infusion, EEG activity was improved in FDP-treated rabbits; in saline-treated rabbits, minimal or no EEG activity was observed. he data suggest the possibility that, at the doses given in this study, FDP is taken up and used as a metabolic substrate by the brain.