Splenomegaly was observed both in male and female Sprague-Dawley rats after 1 week of exposure to CdCl2 (0.6 mg Cd/kg/day). Spleen weight reached about double that in controls by 8 weeks of Cd exposure. Histopathological examination of the enlarged spleen revealed that iron- and lipid-laden histiocytes were clustered in the periarterial lymphatic sheath, and the red pulp appeared to be expanded. It is noteworthy that electron microscopy revealed marked poikilocytosis and Heinz body formation in red blood cells (RBCs) in both the sinus and cord. Histiocytes were swollen by a granular substance in the cytoplasm and also many secondary lysosomes. These morphological findings indicate that degradation of damaged RBCs induced by exposure to Cd might be promoted in the spleen and possibly cause splenomegaly. This RBC damage-hemolysis-splenomegaly sequence is also considered to be associated with the etiology of Cd-induced anemia. In addition to the abnormal RBC degradation, nuclei of lymphocytes in the Cd-exposed spleen exhibited high electron density, consistent with a preapoptotic state suggesting the immunosuppressive effect of Cd.