Background: Living organisms face various kinds of environmental stressors every day that affect the immune system. The spleen plays key role in the immune responses. There is increasing interest in the immunological role played by estrogen in females especially in cases of stress and senility. Aim of the work: To study the effect of estrogen administration on the white pulp of the spleen of senile female albino rats and its possible protective role  in case of stress exposure on the immune cells, estrogen receptors distribution and cell apoptosis  within the white pulp of the spleen.  Materials and Methods: Twenty senile female albino rats were divided into four groups (5 rats/group): Group A, negative control that received daily subcutaneous injection (s.c. inj.) of sesame oil for one week, Group B, rats received s.c. estradiol inj. (40µg/kg BW) for one week, Group C, rats were subjected to immobilization stress for three successive days after s.c. sesame oil inj. for one week, Group D, rats received s.c. estradiol inj.one week before the same stress exposure. All rats were sacrificed at the end of the experiment. Spleen samples were processed for light and electron microscopic examination. Paraffin embedded tissues were sectioned and immune stained in the four groups for estrogen receptors detection, CD3 (T lymphocyte immune marker) and CD20 (B lymphocytes immune marker) distribution also immune-staining for apoptosis was performed in the groups subjected to stress. Results: Estrogen administration resulted in immune cell proliferation in lymphoid follicles of the spleen; an increase in both CD3 and CD20 positively stained cells and estrogen receptors. Stress exposure (Group C) resulted in depletion of the splenic lymphoid follicles, weak immune staining for Estrogen Receptors (ER), dense immune staining for apoptosis, weak immune staining for CD3 and CD20 in contrast to the group protected by estrogen (Group D) which showed preserved white pulp follicles, weak staining for apoptosis marker, preserved immune staining for CD3 and CD20 and positive staining for ER. Electron microscopic examination showed the ultrastructure of lymphocytes in Group A, increased plasma cell in Group B, destructed lymphocytes in Group C and preserved lymphocytes in Group D. Conclusion: Estrogen administration showed immune cell stimulation in senile rats. In addition, estrogen injection prior to stress exposure seemed to reduce the hazardous effect of stress on the immune cells of the spleen. Exogenous estrogen treatment may become clinically important to enhance the immune response in senile female patients especially in stress exposure.