Acute intracranial hypertension was induced in cats by progressive inflation of an epidural balloon. Changes in intracranial pressure (ICP), mean arterial pressure (MAP), cerebral perfusion pressure (CPP), heart rate (HR), electroencephalogram (EEG), and pupil size were studied in untreated animals and in animals that had received barbiturates at different stages during the experiment. In animals pretreated with barbiturates, the increase in ICP during balloon expansion was significantly less than in untreated animals (p less than 0.001). The CPP, initially higher in untreated animals, was not significantly different (P less than 0.05) as the mass lesion pressure-volume curve exceeded the inflection point. In the postdeflation period, the untreated animals developed a significant increase in ICP, whereas, in the barbiturate-pretreated group, the ICP returned to preinflation values, suggesting a protective effect of barbiturates against postcompression brain swelling. Barbiturates affected ICP and CPP differently in animals with intracranial hypertension due to the presence of an epidural balloon that was maintained inflated compared to those with postdeflation brain swelling. In the latter group, pentobarbital reduced ICP (p less than 0.05) without significantly decreasing the CPP, whereas, in the mass lesion group, barbiturates failed to reduce the ICP and caused a deterioration in CPP (p less than 0.025). Brain gross pathological changes were significantly less in the pretreated animals as compared with all other groups. The results suggest that if barbiturate treatment is to have therapeutic value, the timing of the therapy and the criteria for its initiation should be determined.