The ultrastructural effects of 400 mg/M2/day of hydrocortisone sc, given alternatively from day 7 through day 19, were studied on the lymphocyte populations in the white pulp of the spleen and in the cortex of the mesenteric lymph nodes of the immunologically immature rat. Results were consistent with both a direct lytic effect of hydrocortisone on small lymphocytes of the nodular cortex of the mesenteric lymph nodes and an indirect effect on small lymphocytes of the periarterial lymphatic sheath (PALS) of the spleen supplied via the thymus. In contrast, medium-sized lymphocytes in the PALS appeared to be unaffected by hydrocortisone, while medium-sized lymphocytes of the nodular cortex of the mesenteric lymph nodes exhibited a temporary depletion of cytoplasmic organelles. Hydrocortisone appeared to depress protein synthesis in these latter cells. The decrease in numbers of lymphoblasts and plasmablasts observed in the nodular cortex of the mesenteric lymph nodes and the white pulp of the spleen is consistent with hydrocortisone interference with proliferation and differentiation of activated B cells.