Patients with nonthyroid illness (NTI) often have reduced serum T3, free T3, T4, and free T4 concentrations. Paradoxically, serum TSH is usually in the normal range. The data suggest a diagnosis of hypothalamic hypothyroidism, in which TSH may have reduced biological activity because TRH, which is necessary for key steps in the glycosylation of TSH, is deficient. To study the glycosylation of TSH in patients with NTI, we measured the serum TSH concentration in 36 such patients hospitalized on our intensive care units and compared the results with those from a group of 18 normal subjects. Serum TSH was measured in 2 assays: 1) a sensitive TSH RIA of unextracted serum (TSH-RIA) and 2) a RIA of serum TSH after its extraction with Concanavalin-A (Con-A), a lectin which binds glycoproteins containing mannose residues in their oligosaccharide side-chains (TSH-Con-A). The ratio of TSH-Con-A to TSH-RIA was significantly reduced in the NTI patients [0.61 +/- 0.03 (+/- SE) vs. 0.89 +/- 0.05 in the normal subjects] due to reduced binding of the TSH to the Con-A. This change was not dependent on the extent of the abnormalities of thyroid hormone levels. The data suggest that the TSH secreted in NTI has altered glycosylation which is associated with reduced biological activity. This finding may explain in part the low serum T4 level in NTI patients in the face of an apparently normal immunoreactive TSH level.