Because bacterial infection is a potential cause of hyperbilirubinemia, some authors suggest that newborns with significant unexplained indirect hyperbilirubinemia should be evaluated for sepsis. We reviewed the charts of 306 newborns admitted to a pediatric ward within 21 days of birth with a diagnosis of indirect hyperbilirubinemia (peak serum bilirubin level 316 +/- 48, range 217 to 498 mumol/L) (18.5 +/- 2.8, 12.7 to 29.1 mg/dL). Ninety percent were fully or partially breast-fed. Sepsis was identified in 0 of 306 newborns (upper 95% confidence limit for the risk of sepsis = 1%). The overwhelming majority of newborns who require readmission to hospital for indirect hyperbilirubinemia are healthy, breast-fed newborns and do not need to be investigated for sepsis. If indirect hyperbilirubinemia is ever the only manifestation of bacteremia or incipient sepsis, it must be a rare event.