Background: Neonatal hyperbilirubinemia manifests itself in first week of life and is an extremely common condition globally. Although the exact underlying pathophysiological mechanisms are not very well delineated, RBC glutathione store and hence the activity of glucose–6–phosphate Dehydrogenase, the key enzyme of Hexose Monophosphate shunt to provide reduced NADP is crucially implicated. Materials & Methods: In this non interventional, cross–sectional, hospital based study, 200 randomly selected, clinically and biochemically confirmed hyperbilirubinemic neonates within their first 148 hours of life were selected as study subjects as per the inclusion and exclusion criteria. ABO grouping & Rh typing was done, serum total and direct bilirubin concentrations were assayed, and RBC G6PD activity measured. Result: The study revealed 6% of hyperbilirubinemic neonates were having G6PD deficiency. But the hyperbilirubinemic neonates with G6PD deficiency were more prone to develop complicated disease so as to be managed by exchange blood transfusion. No specific blood group swas shown to be associated with hyperbilirubinemia although O positive group revealed a slightly higher predilection to G6PD deficiency. Consanguineous marriage was shown to be associated with G6PD deficiency. Conclusion: Present study shows there is relationship between hyperbilirubinemia and G6PD deficiency and this enzyme deficiency is more commonly found in consanguineous marriage.