BACKGROUND: Unconjugated hyperbilirubinemia results from Gilbert syndrome and from antiretroviral therapy (ART) containing protease inhibitors. An understanding of the interaction between genetic predisposition and ART may help to identify individuals at highest risk for developing jaundice. METHODS: We quantified the contribution of UGT1A1*28 and ART to hyperbilirubinemia by longitudinally modeling 1386 total bilirubin levels in 96 human immunodeficiency virus (HIV)-infected individuals during a median of 6 years. RESULTS: The estimated average bilirubin level was 8.8 micromol/L (0.51 mg/dL). Atazanavir increased bilirubin levels by 15 mu mol/L (0.87 mg/dL), and indinavir increased bilirubin levels by 8 micromol/L (0.46 mg/dL). Ritonavir, lopinavir, saquinavir, and nelfinavir had no or minimal effect on bilirubin levels. Homozygous UGT1A1*28 increased bilirubin levels by 5.2 micromol/L (0.3 mg/dL). As a consequence, 67% of individuals homozygous for UGT1A1*28 and receiving atazanavir or indinavir had > or =2 episodes of hyperbilirubinemia in the jaundice range (>43 micromol/L [>2.5 mg/dL]), versus 7% of those with the common allele and not receiving either of those protease inhibitors (P<.001). Efavirenz resulted in decreased bilirubin levels, which is consistent with the induction of UDP-glucuronosyltransferase 1A1. CONCLUSIONS: Genotyping for UGT1A1*28 before initiation of ART would identify HIV-infected individuals at risk for hyperbilirubinemia and decrease episodes of jaundice.