To determine whether slight decreases in serum thyroid hormone concentrations resulted in augmentation of the thyrotropin (TSH) response to thyrotropin-releasing hormone (TRH), TSH responses to TRH were determined before and after 13 days of iodide treatment in 20 normal subjects. Slight reductions in serum thyroxine (t4) and/or triiodothyronine (T3) concentrations and slight increases in basal serum TSH concentrations occurred in normal subjects treated with 50 or 250 mg iodide daily, though serum T4, T3 and TSH concentrations remained within their respective normal range. In contrast, TSH responses to TRH were significantly greater at the end of the iodide treatment period. In the subjects who received 50 mg iodide daily, mean basal serum TSH concentrations were 3.1 and 3.2 muU/ml before and 4.9 and 4.6 muU/ml after iodide. Post-TRH mean peak serum TSH concentrations were 14.2 muU/ml before and 27.4 muU/ml after iodide (P smaller than 0.01). A very similar augmentation of peak serum TSH was found in the subjects who received 250 mg iodide daily (before iodide, peak TSH 17.2 muU/ml; after iodide, peak TSH 28.7 muU/ml). No changes in serum T4, T3 or TSH concentrations or TSH responses to TRH followed iodide administration in 4 thyroxine-treated hypothyroid patients. These results indicate that slight reductions in serum T4 AND T3 concentrations result in increased pituitary sensitivity to TRH, just as small increases in serum T4 and T3 concentrations decrease sensitivity to TRH.