To evaluate the serum protein binding of carbamazepine (CBZ) and its active metabolite carbamazepine-10, 11-epoxide (CBZ-E) in newborns, cord serum was obtained from 20 infants at the time of birth. Each of the samples was spiked to concentrations of CBZ 12 + CBZ-E 3 micrograms/ml, and CBZ 4 + CBZ-E 1 micrograms/ml and then subjected to analysis for total and free drug concentrations. Total drug concentrations were determined by high pressure liquid chromatography (HPLC), and free drug concentrations were determined by ultrafiltration and subsequent HPLC. The mean percentage of CBZ unbound, calculated as (free drug concentration divided by total drug concentration) X 100, was 30.6 and 29.8% at the high and low concentrations, respectively. Results for CBZ-E were 52.0 and 47.5% at the high and low concentrations, respectively. Compared with previously published values for protein binding in older children and adults, neonates appear to bind CBZ to a lesser degree and CBZ-E to the same degree. The lower binding of CBZ suggests that the therapeutic range of total CBZ in neonates may differ from that in older patients; however, this will have to be determined through clinical study. As previously demonstrated in older patients, CBZ and CBZ-E binding was variable. Monitoring of free CBZ serum concentrations in neonates appears advisable because of this variability.