To identify antecedent clinical and health services events in infants (>/=35 weeks gestational age (GA)) who were discharged as healthy from their place of birth and subsequently sustained kernicterus. We conducted a root-cause analysis of a convenience sample of 125 infants >/=35 weeks GA cared for in US healthcare facilities (including off-shore US military bases). These cases were voluntarily reported to the Pilot USA Kernicterus Registry (1992 to 2004) and met the eligibility criteria of acute bilirubin encephalopathy (ABE) and/or post-icteric sequelae. Multiple providers at multiple sites managed this cohort of infants for their newborn jaundice and progressive hyperbilirubinemia. Clinical signs of ABE, verbalized by parents, were often inadequately elicited or recorded and often not recognized as an emergency. Clinical signs of ABE were reported in 7 of 125 infants with a subsequent diagnosis of kernicterus who were not re-evaluated or treated for hyperbilirubinemia, although jaundice was noted at outpatient visits. The remaining infants (n=118) had total serum bilirubin (TSB) levels >20 mg per 100 ml (342 micromol l(-1); range: 20.7 to 59.9 mg per 100 ml). No specific TSB threshold coincided with onset of ABE. Of infants <37 weeks GA with kernicterus, 34.9% were LGA (large for gestational age) as compared with 24.7% of term infants (>37 weeks GA). Although >90% mothers initiated breast-feeding, assessment of milk transfer and lactation support was suboptimal in most. Mortality was 4% (5 of 125) in infants readmitted at age </=1 week. Along with a rapid rise of TSB (>0.2 mg per 100 ml per hour), contributing factors, alone or in combination, included undiagnosed hemolytic disease, excessive bilirubin production related to extra-vascular hemolysis and delayed bilirubin elimination (including increased enterohepatic circulation, diagnosed and undiagnosed genetic disorders) in the context of known late prematurity (<37 weeks), glucose 6-phosphate-dehydrogenase deficiency, infection and dehydration. Readmission was at age </=5 days in 81 of 118 (69%) infants and <10 days in 101 of 118 (86%) infants. TSB levels were </=35 mg per 100 ml (598 micromol l(-1)) in 46 (39%) infants, of whom one died before exchange transfusion, one was untreated and one was lost to follow-up. Timely and efficacious bilirubin reduction interventions defined by 'crash-cart' initiation of immediate intensive phototherapy and urgent exchange transfusion were accomplished in 11 of 43 infants, which were compared with 12 of 43 infants in whom a timely exchange sometimes could not be accomplished. No overt sequelae were found in 8 of 11 infants (73%) treated with a 'crash-cart' approach compared with none without sequelae when exchange was delayed by pre-admission delays, technical factors or need to transfer to a tertiary facility. None of the remaining 20 of 43 infants treated only with phototherapy escaped sequelae. Regardless of age at readmission and intervention, infants with peak measured TSB >35 mg per 100 ml had post-icteric sequelae (n=73). There was a narrow margin of safety between birthing hospital discharge or home birth and readmission to a tertiary neonatal/pediatric facility. Progression of hyperbilirubinemia to hazardous levels and onset of neurological signs were often not identified as infant's care and medical supervision transitioned during the first week after birth. The major underlying root cause for kernicterus was systems failure of services by multiple providers at multiple sites and inability to identify the at-risk infant and manage severe hyperbilirubinemia in a timely manner.