Cyclosporin A (CsA), a potent immunosuppressive drug, caused organ-specific autoimmune disease, such as gastritis with anti-parietal cell autoantibodies or oophoritis with anti-oocyte autoantibodies, in BALB/c mice when the drug was administered daily for 1 wk to newborns. Administration to adult mice did not. CsA abrogated the production of L3T4+ T cells and Lyt-2+ T cells in the thymus. Consequently, these T cells were substantially depleted from the peripheral lymphoid organs, especially when the drug was administered from the day of birth. Autoimmune disease was prevented when CsA-treated newborn mice were inoculated with splenic T cells from normal syngeneic mice. However, removal of the thymus immediately after neonatal CsA treatment produced autoimmune disease with a higher incidence and in a wider spectrum of organs, i.e., thyroiditis, sialoadenitis of the salivary gland, gastritis, insulitis of the endocrine pancreas, adrenalitis, oophoritis, or orchitis. Each autoimmune disease was accompanied by the development of circulating autoantibodies specific for the corresponding organ Ag. Immunopathology of these autoimmune diseases was quite similar to that of human organ-specific autoimmune diseases.