ABSTRACT— We investigated the hepatocellular transferrin receptor expression in 55 human liver specimens with secondary siderosis, with an indirect immunoperoxidase technique on frozen sections using 3 monoclonal anti-transferrin receptor antibodies. For comparison, specimens were also stained with the monoclonal antibody BK 19.9, recognizing an antigen which is biochemically similar to the transferrin receptor, and with a monoclonal antibody against the epidermal growth factor receptor. The degree of iron overload was estimated semi-quantitatively, taking into account hepatocellular and Kupffer cell iron deposition. In 47 out of 55 specimens hepatocellular transferrin receptor expression was present. The positivity was predominantly localized on hemosiderin-free hepatocytes. With increasing hepatocellular iron deposition, the proportion of cases with absent transferrin receptor immunoreactivity increased. This supports the previously reported disappearance of hepatocellular transferrin receptor expression in primary hemochromatosis cases with severe iron deposition. However, the transferrin receptor negative cases included four specimens in which Kupffer cell iron deposition clearly exceeded hepatocyte iron load. This finding suggests that in addition to hepatocellular iron load other factors may regulate the expression of parenchymal transferrin receptors in iron overload diseases. These may include plasma levels of various iron sources and/or Kupffer cell iron load. The iron deposition did not influence the staining of the hepatocellular epidermal growth factor receptor nor the Kupffer cell staining by the BK 19.9 antibody. This confirms the specificity of the findings concerning the behaviour of the transferrin receptor in secondary siderosis.