Background and aims: Polymorphisms of UGT1A1 gene may contribute to neonatal hyperbilirubinemia (NNH). This study analyzes the role of seven variants of UGT1A1 gene and certain clinical risk factors in NNH. Methods: This was a prospective case control study which included 247 cases. (serum bilirubin ≥15 mg/dl) and 278 control (serum bilirubin T variant was found in 44(17.8%) cases and 22(7.9%) controls (OR 2.5; 95% CI 1.46-4.34). CAT box insertion (CAT)1 → (CAT)2 was seen in 5(2.1%) cases and 1(0.4) control (OR 5.7; 95% CI 0.6-49.3). TATA box variant (TA)6→(TA)7 was detected in151 (61.2%) cases and 141 (50.7%) controls (OR1.42;95% CI 1.06-2.13). 211G>A variant was seen in 13 (5.3%) cases and 5(1.8%) controls (OR3.03;95% CI1.06-8.63). 1456 T>G variant was found in one case and none in controls while 686C>A and 1091 C>T variants were not detected in any case or control newborns. Compound variations of UGT1A1 gene such as -3297 G >T and 211G>A, -3297G>T and (TA)6→(TA)7, and 211G>A and(TA)6→(TA)7 significantly increased the risk of hyperbilirubinemia. Logistic regression analysis showed prematurity, ABO incompatibility, sepsis, weight loss ≥10%, and -3297G>T, CAT box insertion and TATA box variants as significant risk factors for NNH. Conclusion: Variants of UGT1A1 gene, singly or in combination, contribute significantly to neonatal hyperbilirubinemia in Indian population.