Hyperbilirubinemia is probably the most frequently diagnosed and treated condition in the human newborn. Treatment is aimed at preventing the entry of bilirubin into the brain, because of the risk of permanent neurologic damage. The mode by which bilirubin enters the brain, its metabolic fate after entry, and the sites of toxic action are unknown. Using an osmotic stress, we opened the blood-brain barrier in rats, permitting the entry of albumin-bound bilirubin, and thereby creating an animal model of human kernicterus. We performed a pharmacokinetic study of the clearance of bilirubin from the brain. Contrary to expectations from human clinical observations, the clearance of bilirubin was very rapid, with a half-time of 1.6 hours. This half-time was the same as that for clearance from the serum, suggesting that brain bilirubin was removed by transport or diffusion back into the general circulation. Thus, in the undamaged rat brain, bilirubin is rapidly cleared. The potential for clearance of bilirubin from human neonatal brain should be considered.