Data from the whole-body hypothermia trial was analyzed to examine the effects of phenobarbital administration prior to cooling (+PB) on the esophageal temperature (T
e) profile, during the induction phase of hypothermia. A total of 98 infants were analyzed. At enrollment, +PB infants had a higher rate of severe hypoxic-ischemic encephalopathy and clinical seizures and lower T
e and cord pH than infants that have not received phenobarbital (–PB). There was a significant effect of phenobarbital itself and an interaction between phenobarbital and time in the T
e profile. Mean T
e in the +PB group was lower than in the –PB group, and the differences decreased over time. In +PB infants, the time to surpass target T
e of 33.5°C and to reach the minimum T
e during overshoot were shorter. In conclusion, the administration of phenobarbital before cooling was associated with changes that may reflect a reduced thermogenic response associated with barbiturates.