An 11-month-old boy with multiple surface anomalies and respiratory distress due to upper airway narrowing developed generalized tonic seizures coinciding with apnea. The ictal electroencephalography showed an abrupt onset of right-sided unilateral rapid activity with increasing amplitude followed by bursts of spike and wave complexes. The seizures were completely controlled with non-intravenous high-dose phenobarbital therapy. The serum level of phenobarbital at seizure control was 8 microg/ml. The serum level of phenobarbital peaked as high as 123 microg/ml; the patient developed neither liver function abnormality nor hypotension which necessitated any pressor agents. Although the patient was intubated, spontaneous respiration was intact after seizure control. Extubation, however, failed twice because of diminished cough reflex. After decrease of the phenobarbital dose and the development of drug tolerance, the patient was successfully weaned from respiratory support. High-dose phenobarbital therapy is effective for refractory epilepsy in patients complicated by respiratory distress. Although it was reported that respiratory depression was not severe with high-dose phenobarbital therapy, respiratory status may worsen in such patients due to the diminished cough reflex. Therefore the careful and prolonged management is essential.