To investigate the potential role of drug therapy in preventing or exacerbating seizure-related brain injury in the prepubescent brain, we administered kainic acid to rats at postnatal day 35. Therapy with daily phenobarbital was started directly before or 1 day after kainic acid was administered, and was continued through postnatal day 153. Rats receiving phenobarbital had therapeutic concentrations during most of the 24-hour dosing period, but also experienced supratherapeutic peak concentrations. The animals were subsequently tested using the water maze (a measure of visuospatial memory), open field (a measure of activity level), and handling tests (a measure of emotionality). The frequency of spontaneous recurrent seizures was monitored during and after phenobarbital therapy. Kainic acid resulted in status epilepticus on postnatal day 35 in all the rats that received it but those receiving phenobarbital first manifested a shorter and less severe status epilepticus as compared to the rats given kainic acid alone. Rats starting phenobarbital immediately before kainic acid was administered did not differ from control rats on behavioral testing and had no subsequent spontaneous recurrent seizures and no histological lesions. Rats receiving kainic acid alone performed significantly poorer than did control rats in the water maze, were more aggressive, had histological lesions, and manifested spontaneous recurrent seizures. As compared to the group treated only with kainic acid, rats receiving kainic acid followed by phenobarbital at postnatal days 36 to 153 manifested similar aggressiveness and histological lesions, similar frequency of spontaneous recurrent seizures after phenobarbital taper, and even greater disturbances in memory, learning, and activity level. These results demonstrate that kainic acid–related injury can be prevented by a medication working through inhibitory mechanisms; that structural and functional damage in the prepubescent brain can be prevented through strategically timed pharmacotherapy; and that treatment of spontaneous recurrent seizures alone with daily exposure to phenobarbital does not decrease, and may actually exacerbate, damage in the kainic acid model.