Immunosenescence is generally related to weaker immune responses since, elderly individuals do not respond to immune challenge as strongly as the youngs. Spleen is the largest secondary lymphoid organ present almost in all vertebrates. In addition of its skill as a main part of immune system, it serves also as a graveyard for old damaged red blood cells, storage of blood as well as production of antibodies and keeping bodily fluids in balance. So, the present study aims to elucidate its complex histological organization in two mice strains outbred (CD-1) and inbred (Balb/C) throughout their different age groups. Spleen in both mice strains is consisted of two histologically distinct components, red pulp and white pulp vastly different in their architecture vascular organization and cellular composition. Spleen weight consequently splenic index significantly amplified, and diagnosed as splenomegaly, with progression of mice age from 2 to 12 months especially in individuals given Poly I:C acid (400µg/100g b.w.). The elderly as well as treated mice showed irregular splenic architecture with more fibrous trabecula, and extra-large sinusoid spaces throughout the splenic parenchyma to the degree that, limits between white and red pulp disappeared. Furthermore, much decrease of lymphocytes population due to cell progressive nuclear pyknosis and subsequently necrosis and cell degeneration at the olders of 12 month age of both strains, especially those received Poly I:C acid.