The effect of thyroid hormone deficiency on plasma immunoreactive somatomedin-C concentrations, growth hormone (GH) secretion in response to provocative stimuli, and the plasma somatomedin-C response to exogenous GH was studied in patients with primary hypothyroidism. Plasma Somatomedin-C concentrations were below the 95% confidence interval in 11 of 12 hypothyroid patients (mean +/- SD = 0.27 +/- 0.14 U/ml). With thyroid hormone therapy the mean plasma somatomedin-C level increased four-fold (1.00 +/- 0.43 U/ml). The capacity to secrete GH in response to pharmacological agents was impaired in 3 of the 6 hypothyroid patients tested and normal in the remainder. When the same 6 patients were given a single intramuscular injection of GH (0.1 U/kg) plasma somatomedin-C concentrations increased four-fold by 28 h after the injection. The magnitude of the somatomedin-C response was equal to or greater than that reported for euthyroid GH deficient subjects treated similarly. This study shows that plasma somatomedin-C concentrations are diminished by hypothyroidism. The decreased somatomedin-C levels do not appear to result from resistance to the stimulatory effect of GH, but may be either a result of diminished GH secretion or may be due to direct effects of hypothyroidism upon somatomedin production.