In two separate studies, in which two different treatment regimens of Sn-protoporphyrin were used, a total of 69 control and 53 treated infants were studied to determine whether this potent inhibitor of the enzyme, heme oxygenase, could ameliorate the severity of the hyperbilirubinemia which develops in term babies with direct Coombs-positive ABO incompatibility. The results indicate that Sn-protoporphyrin can, in appropriate doses, moderate the postnatal rate of increase of plasma bilirubin levels and diminish the intensity of hyperbilirubinemia in treated babies. In addition, a decreased use of phototherapy in Sn-protoporphyrin-treated infants was observed. No rebound hyperbilirubinemia was detected during the six- to eight-day period after Sn-protoporphyrin administration. The plasma clearance (t1/2) of Sn-protoporphyrin was much faster in newborns than in adults (approximately 1.6 hours v 3.5 hours, respectively). The incidence of clinical side effects in the 53 Sn-protoporphyrin-treated infants was limited to the development of transient erythema during the use of concurrent phototherapy in two babies. In both infants this reaction subsided completely without sequelae. The use of Sn-protoporphyrin or related synthetic heme analogues to diminish the severity of hyperbilirubinemia in newborn infants merits further study because inhibition of the rate-limiting enzyme in the catabolism of heme to bilirubin may prove to be a useful therapeutic approach in the clinical management of neonatal hyperbilirubinemia, especially in settings in which, for social or economic reasons, other treatment modalities are not available.