The effects of long-term administration of very large doses of Sn-protoporphyrin on hematological indices, histological changes, plasma bilirubin levels, tissue heme oxygenase activity, and activities of heme biosynthetic enzymes, were examined in genetically anemic mutant mice with hemolytic anemia (sphha/sphha). Long-term weekly treatment with Sn-protoporphyrin (100 mumol/kg body weight for 32 wk) did not alter hematological indices, histological findings, or enzyme activities related to heme biosynthesis, even though it resulted in sustained decreases in microsomal heme oxygenase activity in the liver, kidney, and spleen, and a prolonged decrease in plasma bilirubin concentration. Inhibition of heme oxygenase did not alter the level of cytochrome P-450 in the liver and the kidney. The results indicate that long-term treatment with massive doses of Sn-protoporphyrin suppresses bilirubin formation but does not produce significant histopathological changes or appreciably interfere with heme synthesis, in this strain of genetically anemic mice. These findings provide further support for the idea that suppression of heme degradation to bile pigment by the inhibition of heme oxygenase may prove useful to the prevention of severe hyperbilirubinemia in humans.