Plasma cyclic AMP and cyclic GMP levels were studied in a group of normal subjects and 10 subjects with hyperthyroidism. In the control group, mean plasma cyclic AMP levels were 15.3 +/- 1.3 nmol/l (SEM), and plasma cyclic GMP levels were 9.4 +/- 0.58 nmol/l (SEM). In untreated hyperthyroid subjects, both plasma cyclic AMP and cyclic GMP levels were significantly elevated above normal with mean values of 35.0 +/- 2.4 nmol/l (SEM) (P less than 0.001) and 14.7 +/- 0.2 nmol/l (SEM), (P less than 0.001), respectively. Six of the hyperthyroid subjects were re-studied when they became euthyroid; plasma cyclic nucleotide concentrations all fell within the normal range. To evaluate the relative contribution of triiodothyronine and thyroxine to elevated plasma cyclic nucleotide levels, two hyperthyroid subjects were treated with propylthiouracil and iodide. Plasma cyclic nucleotide levels were normalized when plasma triiodothyronine levels declined to normal range, at the time when plasma thyroxine levels were still elevated. These preliminary data suggest that increased triiodothyronine production is responsible for the increased cyclic nucleotide levels in hyperthyroidism.