A previous retrospective study showed an increased frequency of neonatal hyperbilirubinemia at high altitude in Colorado. In a prospective study we found that 39% of newborns at 3100 m altitude vs 16% at 1600 m exhibited hyperbilirubinemia, defined as a day 3 serum bilirubin level of 205 mumol/L or higher. Increased bilirubin production at 3100 m vs 1600 m was shown by increased levels of corrected carboxyhemoglobin. This finding was supported by increased erythropoietin and bilirubin values in cord blood and increased hematocrit values at day 3 among infants at 3100 m vs 1600 m. The sustained elevation in bilirubin for breast-fed vs formula-fed infants at 1600 m was observed for both feeding types at 3100 m. The findings suggested that there is a hematologic response to decreased oxygen availability at high altitude, resulting in increased bilirubin production accompanied by delayed bilirubin clearance.