Yellow staining of central nervous system (CNS) nuclei occurs in the brains of some neonates, despite low levels of serum bilirubin. Two conditions appear to be important in the evolution of this form of kernicterus: prematurity and asphyxia. In a seven year retrospective study of a large neonatal autopsy population, 102 cases had kernicterus as indicated by selective macroscopic yellow staining and microscopic damage within specific CNS nuclei. Neuropathological study disclosed minor variations and numerous similarities in the manifestations of kernicterus in the asphyctic premature neonate with low levels of serum bilirubin, as compared to kernicterus in the full-term neonate with high levels of serum bilirubin. Acidosis, hypoxia, hyperoxia, hypothermia and sepsis have been considered significant risk factors, but recent comparative clinical studies have not defined predictive indices. Analysis of this disorder is difficult because of the concurrence of other complications of asphyxia and its pathological correlates in premature infants. Diagnostic difficulties are also compounded by variations in the definitions of kernicterus as used by different investigators.