The histologic effects of the alternate-day hydrocortisone therapy (400 mg/M2 from day 7 to day 19 after birth) were studied on the mesenteric lymph nodes of immunologically immature rats. In rats sacrificed 2 days following the cessation of therapy, depletion of lymphocytes of the thymus-independent area was apparent. Smaller lymphocytes were more susceptible to the effect of hydrocortisone than larger ones. The absence of primary follicles, normally present at this age, suggested a possible retardation in development of the immune system. B lymphocytes appeared to be the target of the direct lymphocytolytic effect of hydrocortisone. In rats sacrificed 23 days following the treatment, immunological maturity was achieved, indicating the reversibility of the hydrocortisone effect.