The effects of cyclosporine (CyA) on lymphoid organs and the ability of prolactin to counteract these effects were investigated in adult male rats. Two methods to induce hyperprolactinemia were used: implantation of a pituitary into the kidney capsule, or exposure to diethylstilbestrol (DES) via subcutaneous silastic capsules which remained in place until the animals were killed (DES-In) or were removed 24 days prior to sacrifice (DES-Out). Hyperprolactinemic rats had decreased body and spleen weights; these reductions were greater in animals with more marked hyperprolactinemia. The weight of the thymus did not change in pituitary-grafted or DES-Out rats, but was reduced in DES-In rats. The number of peripheral white blood cells (PWBCs) was decreased to a greater extent in DES-treated than in grafted animals. Blood white cell counts were not changed in grafted animals. The number of lymphocytes in the thymus was not changed by the grafts, but was decreased in DES-In rats; this effect was reversed by removal of the capsules (DES-Out rats). However, the DES-treated animals had a smaller number of splenic lymphocytes than did controls. The natural killer (NK) activity of spleen lymphocytes was not altered in hyperprolactinemic rats. Treatment with CyA did not modify body or spleen weights or the number of lymphocytes in the thymus in sham-operated rats; however, CyA reduced thymus weight and the number of PWBCs. CyA did not affect body, spleen or thymus weights of the animals bearing empty capsules, but diminished the number of lymphocytes in the thymus and the spleen, without modifying the number of PWBCs or the NK activity of spleen lymphocytes. In hyperprolactinemic animals CyA induced no significant changes in body or lymphoid organ weights, in the number of PWBCs or of thymic or splenic lymphocytes, or in NK activity. Unlike its effects in DES-treated animals, CyA treatment eliminated the increase in plasma prolactin levels in pituitary-grafted rats; prolactin levels in control rats were not changed after CyA therapy. These results suggest that chronic hyperprolactinemia has immunosuppressive effects on lymphoid organs, without affecting NK activity of spleen lymphocytes, and that CyA affects prolactin secretion from ectopic pituitary transplants, but does not affect secretion of this hormone by the hyperplastic pituitaries of DES-treated rats.