Both the basal TSH concentration and the TSH response to iv TRH administration are noted to be decreased at the peak of an acute critical illness. Moreover, an impaired release from hypothalamus has been documented in rats with uncontrolled diabetes, suggesting hypothalamic dysfunction in a non-thyroidal illness. However, the exact inference and mechanism of this impaired TSH secretary pattern is not well defined in humans during a non-thyroidal illness. Therefore, this study assessed hypothalamic pituitary thyroid axis by determination by T4, T3, and T3 resin uptake prior to and TSH concentrations, prior to, as well as following, iv TRH administration at an interval of 30 min up to 2 hours on three successive mornings during a severe, critical, fatal illness in five previously known euthyroid subjects. TSH response to iv TRH administration was expressed as a maximal absolute change (delta TSH) and a cumulative response (CR TSH), calculated as the sum of changes from the basal level at each specific time period for up to 120 min. Serum T4, T3 and TSH concentrations on day 1 of the TRH administration were significantly lower than normal values as well as the values documented previously in the same individuals prior to hospitalization. T3 resin uptake was increased simultaneously. Moreover, serum T4, T3, and T3 resin uptake remained significantly unaltered on three successive days of iv TRH administration. However, basal serum TSH rose significantly with a parallel TSH response to iv TRH administration, as reflected by a progressive rise in delta TSH as well as CR TSH over this three-day period, with normalization of the TSH responses by the third day. Therefore, impaired TSH secretary pattern and altered thyroid hormone concentrations noted in subjects with acute critical illness may be attributed to the presence of a transient hypothalamic hypothyroidism.