Although phenobarbital is the most widely used drug to control seizures, dosage guidelines are not available for infants of varying gestational ages. The primary objective of this study was to develop age specific dosage guidelines for phenobarbital in newborn infants with seizures. Fifty-one patients (27 premature infants, gestational ages 27 to 38 weeks; 24 term infants) receiving phenobarbital, 3 to 6 mg/kg/d were studied during the first month of life. Multiple serum concentrations were determined in each patient during extended therapy. Trough serum concentration of phenobarbital ranged from 12.5 to 50.2 mcg/mL. Phenobarbital serum concentrations were within therapeutic range (15 to 40 mcg/mL) in 99 of 114 measurements at a maintenance dose of 3.5 to 4.5 mg/kg/d. The remaining 15 measurements were made in infants, greater than 35 weeks' gestation and required phenobarbital doses of 4.0 to 5.0 mg/kg/d to achieve therapeutic serum concentration. These data suggest that the initial maintenance dose of phenobarbital during the first month of life should be 3.5 to 4.5 mg/kg/d in infants less than or equal to 35 weeks and 4.0 to 5.0 mg/kg/d in those greater than 35 weeks' gestation. Term infants with asphyxia had higher trough serum concentration than those without asphyxia (P less than 0.005). In nine infants, trough serum concentration normalized for dose decreased substantially during a 3-weeks period (P less than 0.0005). This suggests that phenobarbital serum concentration should be monitored frequently during the first month of life.