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Genome-wide association studies (GWASs) have identified loci contributing to total serum bilirubin level. However, no exome-wide approaches have been performed to address this question. Using exome-wide approach, we assessed the influence of protein-coding variants on unconjugated, conjugated, and total serum bilirubin levels in a well-characterized cohort of 773 ambulatory elderly subjects from Italy. Coding variants were replicated in 227 elderly subjects from the same area. We identified 4 missense rare (minor allele frequency, MAF<0.5) and low-frequency (MAF, 0.5–5) coding variants located in the first exon of the UGT1A1gene, which encodes for the substrate-binding domain (rs4148323 MAF=0.06; p.Gly71Arg, rs144398951 MAF=0.06; p.Ile215Val, rs35003977 MAF=0.78; p.Val225Gly, and rs57307513 MAF=0.06; p.Ser250Pro). These variants were in strong linkage disequilibrium with 3 intronic UGT1A1variants (rs887829, rs4148325, rs6742078), which were significantly associated with total bilirubin level (P=2.34×10−34, P=7.02×10−34, and P=8.27×10−34), as well as unconjugated, and conjugated bilirubin levels. We also identified UGT1A6variants in association with total (rs6759892, p.Ser7Ala, P=1.98×10−26; rs2070959, p.Thr181Ala, P=2.87×10−27; and rs1105879, p.Arg184Ser, P=3.27×10−29), unconjugated, and conjugated bilirubin levels. All UGT1A1intronic variants (rs887829, rs6742078, and rs4148325) and UGT1A6coding variants (rs6759892, rs2070959, and rs1105879) were significantly associated with gallstone-related cholecystectomy risk. The UGT1A6variant rs2070959 (p.Thr181Ala) was associated with the highest risk of gallstone–related cholecystectomy (OR, 4.58; 95 CI, 1.58–13.28; P=3.21×10−3). Using an exome-wide approach we identified coding variants on UGT1A1and UGT1A6genes in association with serum bilirubin level and hyperbilirubinemia risk in elderly subjects. UGT1A1intronic single-nucleotide polymorphisms (SNPs) (rs6742078, rs887829, rs4148324) serve as proxy markers for the low-frequency and rare UGT1A1variants, thereby providing mechanistic explanation to the relationship between UGT1A1intronic SNPs and the UGT1A1 enzyme activity. UGT1A1and UGT1A6variants might be potentially associated with gallstone-related cholecystectomy risk.