In an attempt to develop a model relating several clinical indices of thyroid hormone action to serum free T3 concentration and the estimated occupancy of nuclear T3 receptors, we have performed serial studies in 19 patients with hyperthyroidism and 16 patients with hypothyroidism both before and after the initiation of standard treatment. With increasing serum free T3 concentrations, we observed gradual increases in mean heart rate and sleeping heart rate, reaching, respectively, mean plateau values of 109 and 99 beats/min. As expected, with increasing serum T3 concentrations, a hyperbolic fall in serum cholesterol, serum creatine phosphokinase activity (CPK), and Achilles tendon reflex relaxation time (ATRT) was noted. Nuclear occupancy was calculated from the plasma T3 concentration and the physicochemical characteristics of human nuclear receptor sites, as determined in other studies. Nuclear T3 occupancy was found to be linearly related to mean heart rate (r = 0.81) and to sleeping heart rate (r = 0.77). A linear relationship was also observed between the reciprocals of serum cholesterol (r = 0.80) and CPK (r = 0.73) concentrations and the reciprocal of ATRT (r = 0.86). These inverse relationships suggest that T3 simulates the fractional removal of cholesterol, CPK, and, perhaps, some substance causing prolongation of ATRT. We believe the linear relationships between nuclear occupancy and the clinical indices are consonant with the biological relevance of nuclear T3 receptors in man.