ABSTRACT. Antibody-dependent cell-mediated cytotoxicity (ADCC) is the process by which antibodies interact with killer cells to effect cell lysis, whereas natural killing (NK) refers to the ability of peripheral blood killer cells to lyse target cells in the absence of specific antibody. The purpose of the present study was to determine if either NK cells or ADCC might play a role in the development of Hashimoto’s thyroiditis (HD) by testing the ability of killer cells to cause lysis of K562 erythroleukemia tumor cells and human thyrocytes in the presence and absence of serum from normal and HD patients. Using K562 target cells, NK activity was 70 ± 4% (mean ± SEM) for HD effector cells and 66 ± 5% for normal effector cells at an effector to target ratio of 100:1. Similarly, with thyrocytes as targets, effector cells from HD patients (38 ± 3%) and normal subjects (34 ± 5%) caused comparable lysis (at an effector to target ratio of 100:1). Using K562 target cells, ADCC was 35% when effector cells from HD or normal subjects were coincubated with either normal or HD sera. Using thyrocyte target cells, lysis was about 25 30%, but, again, no differences were found between HD and normal effector cells or serum. There was a significant correlation between lysis for K562 and thyrocyte target cells, but there was no significant correlation between the titer of serum antithyroid microsomal antibodies and specific lysis. Intrathyroidal lymphocytes and peripheral lymphocytes from one patient with HD caused comparable lysis of labeled thyrocyte targets, as did normal peripheral lymphocytes. We conclude that ADCC and NK activities in peripheral lymphocytes were normal in HD patients and, therefore, may not have a primary role in mediating thyrocyte destruction in Hashimoto’s thyroiditis.