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Factors modulating host resistance to Histoplasma capsulatum are only partially understood. The role of iron-binding proteins in infectious diseases has been an area of recent in-depth investigation. The present study reaffirmed the necessity of iron for growth of H. capsulatum. Transferrin saturation was found to be of importance in withholding iron, and antigen-specific antibody had no added effect. Serums of patients with various clinical classes of histoplasmosis were found to exhibit abnormalities in iron metabolic parameters. However, based on transferrin saturation data, iron withholding by transferrin does not appear to be a significant host defense mechanism in vivo. Further studies presented herein suggest a protective effect of phagocytosis and sequestration by the macrophage-phagocyte system.