The thyrotropin (TSH) response to thyrotropin-releasing hormone (TRH) (200 μiv) was determined in 80 surgical patients with nontoxic multinodular goiter. The TSH reserve was normal in 55 and elevated in 8 patients. No TSH response to TRH (ΔTSH ⋚ 1 μU/ml) was detectable in 17 patients (21%). Individual and mean serum T4, FT4I and serum T3 values did not differ from normal in 13 of the TRH unresponsive patients; in 4 patients FT4I or serum T3 was marginally elevated. No statistical differences were noted for I131-uptake, PBI131 and conversion rate between controls and TRH unresponsive patients. All patients who failed to respond to TRH were euthyroid on clinical evaluation. Goiters were large multinodular and long-standing in most instances. In 12 tested subjects TRH responsiveness recovered following partial thyroidectomy. In 3 of 7 TRH unresponsive euthyroid patients tested 9–12 days post surgery a transient lack of TSH to respond to TRH was observed. Recovery of TRH responsiveness was accompanied by a significant (P < 0,02) decrease in serum T4 and FT4I in the euthyroid range, whereas no change in serum T3 occured. It is suggested that TRH unresponsiveness represents a state of preclinical hyperthyroidism maintained by autonomously functioning goiter compartments.