Tertatolol is a new potent beta-blocker without intrinsic sympathomimetic activity and lacking beta 1/beta 2 receptor subtype selectivity. Tertatolol was found in vitro to be a competitive inhibitor of beta-adrenergic receptors in competitive binding experiments. However, the density of beta-adrenergic receptors on intact human lymphocytes preincubated with tertatolol was reduced. When given at therapeutic doses (5 mg/day) to human volunteers, it induced a reduction in the number of beta-adrenergic receptors (Bmax) without any change in the affinity (KD) for intact lymphocytes (beta-adrenergic receptors were measured by the specific binding of 3H-CGP 12177). This effect was seen 7 h (-54%), 24 h (-35%) and 48 h (-30%) after a single drug dose. A similar receptor reduction was observed 7 h (-42%), 24 h (-37%) and 48 h (-15%) after 14 daily doses of the drug. In parallel, the pharmacological efficacy of the drug was evident from the reduction in heart rate in supine and upright positions and after submaximal exercise; heart rate was reduced to the same extent after single or repeated drug doses. The reduction in receptor number correlated with the reduction in heart rate in both the supine (p less than 0.001) and upright (p less than 0.01) positions and after exercise (p less than 0.02). We conclude that tertatolol, besides competitively inhibiting beta-adrenergic receptors, induces a marked and lasting decrease in beta-adrenergic receptor number. This effect may be important for the beta-blocking effects of this drug.