Background and Aims: Bilirubin encephalopathy/ker-nicterus is very rare in adults. This study is aimed to inves-tigate the clinical manifestations and genetic features of two patients with UGT1A1-related kernicterus. Methods: Sanger sequencing analysis was performed to identify UGT1A1 gene mutations in the patients and their families. Bioinfor-matics analysis was used to predict the potential functional effects of novel missense mutations. Clinical manifestations and biochemical parameters were collected and analyzed. Results: Two patients with Crigler-Najjar syndrome type II (CNS2) developed kernicterus in adulthood. Sanger se-quencing identified a compound heterozygous mutation in the UGT1A1 gene in patient 1, which was inherited from his mother (G71R) and his father (c.-3279T>G; S191F). Patient 2 carried three heterozygous mutations, namely G71R, R209W and M391K; among which, the M391K mu-tation has not been reported before. Multiple prediction software showed that the M391K mutation was pathogenic. Symptoms were relieved in the two patients after pheno-barbital and artificial liver support treatment. Patient 1 also underwent liver transplantation. Conclusions: Adults with CNS2 are at risk for kernicterus. Phenobarbital treatment is beneficial for maintaining bilirubin levels and preventing kernicterus.