<b><i>Background:</i></b> Glucose-6-phosphate dehydrogenase (G6PD) deficiency is a common enzyme deficiency affecting more than 300 million individuals worldwide. Extreme neonatal hyperbilirubinemia, with its severe sequelae of bilirubin neurotoxicity and the potential of death, is the most devastating manifestation of G6PD deficiency. In a recent review of Favism, Luzzatto and Arese state that the pathophysiology of jaundice in G6PD-deficient neonates is different from that of favism, as there is little evidence of hemolysis in these infants. <b><i>Objectives:</i></b> To explore the role of hemolysis in neonatal hyperbilirubinemia associated with G6PD deficiency. <b><i>Methods:</i></b> Previously published works including studies of endogenous production of carbon monoxide (CO), an index of heme catabolism, in hyperbilirubinemic G6PD-deficient neonates were reviewed to determine the role of hemolysis in this condition. <b><i>Results:</i></b> Three studies demonstrated that endogenous CO production is elevated in G6PD-deficient neonates with extreme hyperbilirubinemia. <b><i>Conclusions:</i></b> Hemolysis is an important pathogenetic factor in G6PD deficiency-associated neonatal hyperbilirubinemia.