The role of anemia in the induction of splenic alterations during pregnancy has been studied in mice and rats. The enlarged spleens of 12 day pregnant CBA mice typically showed dramatic increase in numbers of esterase-positive cells (mainly erythroblasts) and increase in numbers of immunoglobulin-secreting cells. Pregnant Sprague-Dawley rats showed slight enlargement of the spleen, no change in the content of esterase-positive cells, but a clear-cut increase in numbers of Lepehne -stained erythroblasts and immunoglobulin-secreting spleen cells. Virgin mice and rats were made anemic by bleeding or phenylhydrazine-treatment. These animals showed very much the same splenic alterations as those of pregnant mice and rats. In a final experiment pregnant CBA mice were subjected to transfusion of washed syngeneic red blood cells in order to normalize their erythrocyte counts. These mice showed reduced splenomegaly, reduced increase in numbers of esterase-positive cells and reduced numbers of immunoglobulin-secreting cells. It was concluded that pregnancy-associated anemia ( erythropenia ) is a major reason to the gross change in size and cell content of the maternal spleen.