Administration of estrogens to acromegalic patients has been shown to reduce the serum concentrations of bioassayable somatomedin and to cause improvement in clinical status. These effects appear not to result from an effect on the secretion of growth hormone since growth hormone concentrations are not consistently reduced. Using a sensitive radioimmunoassay for somatomedin-C, we have assessed the relationship between the estrogen-induced reduction of somatomedin-C and changes in several indices of disease activity in five acromegalic patients. Statistically significant reductions in serum somatomedin-C (p < 0.02), urinary hydroxyproline (p < 0.05) and the phosphate clearance ratio (p < 0.01) occurred within three days of the institution of treatment with 1 mg ethynyl estradiol daily. Unlike the consistent reduction in serum somatomedin-C erratic changes in growth hormone were observed. The decline in serum somatomedin-C was not due to an estrogen-induced increase in somatomedin-binding proteins since total serum somatomedin-C concentrations measured after treatment of serum with acid also were reduced by estrogen therapy, and the magnitude of this reduction was equivalent to that observed in untreated serum. The study indicates that the reduction of immunoreactive somatomedin-C correlates with estrogen-induced improvement in the metabolic activity of acromegalic patients and suggests that measurement of somatomedin-C may be useful in monitoring the effects of other drugs on this disease.