Thionamides are used in the treatment of Graves' disease (GD) and act mainly by inhibiting the organification of iodide, but also lower the levels of thyroid autoantibodies, sometimes leading to long-term remission. Fas ligand (FasL) induces apoptosis of susceptible cells by cross-linking its own receptor, Fas. While Fas is present in a wide variety of normal tissues, FasL expression is limited mainly to cells of the immune system, where it acts as an effector molecule of cell-mediated cytotoxicity, and to the placenta, brain, eye, and testis where it presumably contributes to their immune-privileged status by eliminating infiltrating lymphocytes. We examined immunohistochemically the presence of FasL in thyroid tissue from 15 glands of thionamide-treated GD patients and in 8 normal thyroid control specimens. We also investigated the presence of FasL in thionamide-treated thyrocytes in vitro and their ability to induce Fas-mediated apoptosis in lymphocytes. We found that FasL expression was very weak to undetectable in normal thyroid tissue and cultured thyrocytes, whereas it was strong in thionamide-treated GD glands and cultured thyrocytes. Methimazole-treated thyrocytes induced FasL-dependent apoptosis in cocultured lymphocytes, whereas methimazole treatment of lymphocytes grown in the absence of thyrocytes had no such effect. We conclude that FasL is highly expressed in follicular cells of thyroid glands obtained from thionamide-treated Graves' patients and may contribute to the immunomodulatory effect of thionamides in this disease.