The relationship between ouabain-sensitive ATPase (Na-K ATPase) activity in erythrocytes and the thyroid status was studied in 36 patients with Graves'' disease and 58 patients receiving L-thyroxine (T4) replacement therapy. Forty normal children served as controls. Total ATPase activity in 4 untreated hypothyroid patients was significantly reduced (11.0 .+-. 4.6 vs. 17.3 .+-. 4.1 .mu.g-P/h per mg-protein, P < 0.01), and Na-K ATPase was undetectable, both of which were normalized after 4 wk of L-T4 therapy. Na-K ATPase in hyperthyroid patients was also decreased (0.9 .+-. 0.8 vs. 4.0 .+-. 2.7, P < 0.01), but was gradually normalized after 3 mo. of euthyroid state. Clinically euthyroid children treated with L-T4 were divided into 2 groups with regard to Na-K ATPase activity, normal and low. Analysis of the possible factors producing this difference revealed that, in primary hypothyroidism, the factor appeared to be the endogenous T4 level, while in patients with dwarfism, the secretory capacity of TSH or TRH was contributory. Na-K ATPase activity in red cells remains within the normal range after L-T4 replacement in the presence of a severe degree of primary hypothyroidism or in association with secondary or tertiary hypothyroidism. Other factors such as the L-T4 dose, duration of the therapy, serum T4 and T3 [triiodothyronine] concentrations, were not significantly different in the 2 groups. Na-K ATPase in red cells is decreased in hyper- or hypothyroid state, restoration of normal activity requires 1-3 mo. of euthryoid period, and it is a sensitive index of peripheral thyroid status over the preceding few months.