A depressive man was evaluated for developing chronic fatigue and cold intolerance, in whom laboratory findings showed decreased thyroid hormone levels (T4, 2.7 micrograms dl-1; T3, 0.76 ng ml-1) with normal blood levels of TSH. A single bolus injection of TRH (500 micrograms) significantly stimulated prolactin secretion, but did not cause an increase in blood TSH levels (basal level, 1.2 microU ml-1 vs. 1.3 microU ml-1 30 min after injection). By contrast, TRH-induced TSH stimulation occurred after repeated injection of TRH for 4 consecutive days (basal level, 1.5 microU ml-1 vs. 5.6 microU ml-1 30 min after injection). Blood thyroid hormone concentrations were restored to normal levels after long-term administration of TRH. Other pituitary functions remained unchanged. A diagnosis of central hypothyroidism due to isolated TRH deficiency was made in this case, and the data presented here indicate that partial resistance of pituitary thyrotrophs to TRH may be associated with depression.