OBJECTIVE Lipid peroxidation, DNA damage and total antioxidant status (TAS) were assessed in neonates with unconjugated hyperbilirubinemia (UCH). METHODS Plasma malondialdehyde (MDA), 8-hydroxy-2-deoxy-guanosine (8-OH-dG) and TAS levels were compared between 64 term newborns with idiopathic UCH and 30 age-matched healthy controls. RESULTS Compared with controls, an overall increase in mean plasma MDA and 8-OH-dG levels and a decrease in TAS level were noted in the UCH group. Within the UCH group, mean plasma MDA level was found to be low in infants with lower bilirubin levels, but a progressive increase was documented above the bilirubin level of 20 mg dl(-1). A significant increase in 8-OH-dG level was documented even at lower bilirubin levels, and a decrease i plasma TAS level was found at bilirubin levels above 16 mg dl(-1). MDA and 8-OH-dG levels were significantly higher, whereas TAS level was significantly lower in five neonates who developed features of acute bilirubin encephalopathy compared with those with normal outcome. Alteration of MDA, 8-OH-dG and TAS levels showed high predictive accuracy for poor outcome. CONCLUSIONS Moderate-to-severe UCH was associated with higher oxidative stress and lower antioxidant defense. Alteration of oxidative stress parameters may be utilized as early predictors for poor outcome. High DNA damage even at lower bilirubin levels suggests possible genotoxic effect of bilirubin in UCH.