Background & Aims: Severe unconjugated hyperbilirubinemia, as occurs in Crigler-Najjar disease and neonatal jaundice, carries the risk of neurotoxicity. This neurotoxicity is related to the increased passage of free bilirubin (UCBfree) the fraction of bilirubin that is not bound to plasma proteins, into the brain. We hypothesized that albumin treatment would lower the UCBfree fraction, and thus decrease bilirubin accumulation in the brain. Methods: We treated chronic (e.g., as a model for Crigler-Najjar disease) and acute hemolytic (e.g., as a model for neonatal jaundice) moderate hyperbilirubinemic Gunn rats with phototherapy, human serum albumin (HSA) or phototherapy + HSA. Results: In the chronic model, adjunct HSA increased the efficacy of phototherapy; it decreased plasma UCBfree and brain bilirubin by 88% and 67%, respectively (p Conclusions: We showed that adjunct HSA treatment decreases brain bilirubin levels in phototherapy-treated Gunn rats. We hypothesize that HSA decreases these levels by lowering UCBfree in the plasma. Our results support the feasibility of adjunct albumin treatment in patients with Crigler-Najjar disease or neonatal jaundice. (C) 2012 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.