Eleven men were fed foods naturally high or low in selenium for 120 d. Selenium intake was stabilized at 47 µg/d for 21 d, then changed to either 13 or 297 µg/d for 99 d, leading to significantly different blood selenium and glutathione peroxidase concentrations. Serum immunoglobulins, complement components, and primary antibody responses to influenza vaccine were unchanged. Antibody titers against diphtheria vaccine were 2.5-fold greater after reinoculation in the high selenium group. White blood cell counts decreased in the high-selenium group and increased in the low-selenium group, resulting primarily from changes in granulocytes. Apparent increases in cytotoxic T-lymphocytes and activated T-cells in the high-selenium group only approached statistical significance. Lymphocyte counts increased on d 45 in the high-selenium group. In vitro proliferation of peripheral lymphocytes in autologous serum in response to pokeweed mitogen was stimulated in the high-selenium group by d 45 and remained elevated throughout the study, whereas proliferation in the low selenium group did not increase until d 100. This study indicates that the immune-enhancing properties of selenium in humans are the result, at least in part, of improved activation and proliferation of B-lymphocytes and perhaps enhanced T-cell function.