These experiments have examined the physical properties and the hepatic uptake of non-transferrin-bound iron, a fraction found in the serum of untreated primary hemochromatosis patients. Ultrafiltration, polyacrylamide gel electrophoresis, and TLC have demonstrated the non-transferrin-bound iron complex to have a molecular weight less than 1000 and to be distinct from free iron and amino acid iron complexes. Hepatic iron uptake from serum containing non-transferrin-bound iron was significantly higher than from the same serum sample from which the abnormal iron had been removed. Non-transferrin-bound iron entering the liver was localized to the lysosomal fraction in the first hour and was subsequently incompletely incorporated into ferritin. The results demonstrated an abnormal uptake of this iron fraction by the liver and suggest that the abnormal serum fraction may contribute to tissue damage by entering the lysosomes.