Background: The gene 211G>A variants, that underlie complex disorders, are characteristically common in the neonatal hyperbilirubinemia. However, it is the contribution of multiple different co-expressed susceptibility genes that individually confer a small increase in risk coupled with environmental factors that generate complex disorder phenotypes. Objective: This study aimed to understand the relation of 211G>A promoter polymorphism in UGT1A1 gene and the risk of hyperbilirubinemia in newborns. Patients and Methods: The study included 50 newborns with hyperbilirubinemia with gestation age of ≥ 37weeks and postnatal age of ≤ 2 weeks with normal birth weight. 34 were males and 16 were females. They were divided into two groups; case group consisting of 30 neonates with the peak of total serum bilirubin (TSB) levels ≥ 16 mg /dl and control group consisting of 20 neonates with the peak total serum bilirubin (TSB) levels <12 mg/dl. Variation status of UGT1A1 genes in our study was determined by direct sequencing or genotype assays. Results: This study showed that UGT1A1 promoter gene polymorphism 211G>A genotype can be used as a novel method to detect susceptibility to indirect hyperbilirubinemia in neonates. Conclusion: Our findings added to the understanding of the significance of UGT1A1 in association with neonatal hyperbilirubinemia in East Delta of Egyptian population. Additionally we are in need for other studies to investigate the protective mechanisms.