Crigler-Najjar syndrome type I (CN-I, MIM #218800) is a rare and severe autosomal disorder. It is caused by deficiency of the liver enzyme responsible for bilirubin elimination, the uridine diphosphate glucuronosyltransferase 1A1 (UGT1A1; EC 2.4.1.17). Biologically, the disease manifests itself with severe and persistent unconjugated hyperbilirubinemia. Kernicterus is a well-known complication of severe unconjugated hyperbilirubinemia in infants and young children, especially in patients with CN-I.Few articles have shown the efficiency of plasmapheresis for extreme hyperbilirubinemia.In this report, we describe the efficiency of plasmapheresis for a rapid control of acute and severe unconjugated hyperbilirubinemia in a 6-year-old CN-I patient who had previously developed kernicterus in the neonatal period. In spite of intensification of phototherapy, the patient developed severe hyperbilirubinemia (up to 830 μmol/l, with bilirubin/albumin ratio at 1.2). With two plasmapheresis procedures, bilirubin serum concentration decreased to 420 μmol/ and bilirubin/albumin ratio to 0.55. Following the acute episode of very severe unconjugated hyperbilirubinemia, the child recovered and neurological examination was unchanged, thus suggesting that plasmapheresis possibly prevented further worsening of kernicterus.