We measured serum concentrations of somatomedin-C by radioimmunoassay in 57 acromegalic patients and compared them with various indicators of disease activity. The mean fasting somatomedin-C concentration was 6.8 U per milliliter (range, 2.6 to 21.7) for the acromegalics and 0.67 U per milliliter (range, 0.31 to 1.4) for 48 normal, fasting adults. The somatomedin-C concentration correlated significantly with: heel-pad thickness (r = 0.73), fasting glucose (r = 0.74), and one-hour postprandial glucose (r = 0.77). In contrast, "glucose-suppressed" growth hormone correlated weakly (r = 0.34, 0.36, 0.34) with these clinical indexes of severity. Fasting growth hormone levels showed no correlation (r = 0.14). Five active acromegalics had "normal" growth hormone levels after glucose suppression, but they had elevated somatomedin-C. In 15 patients studied one year after treatment, changes in somatomedin-C concentrations paralleled the degree of clinical improvement. Measurement of somatomedin-C appears to provide a reliable means for confirming the diagnosis of acromegaly and of clinical disease activity than measurement of growth hormone concentrations.