&NA;The effect of isoproterenol infusion and exercise on R‐wave magnitude was studied in normal subjects and in patients with coronary artery disease. (Group A) Isoproterenol infusion (2 &mgr;g/min/10 min) decreased R‐wave magnitude in ten normal subjects (‐10.8 ± 1.6%, P < 0.001). R‐wave magnitude remained unchanged when isoproterenol was given after propranolol (160 mg) daily for two days (‐0.9 ± 2%). R‐wave magnitude decreased with exercise (‐8 ± 3%, P < 0.05) in five normal subjects but increased with exercise performed after propranolol (160 mg) daily for two days (+11.5 ± 3.5%, P < 0.05). (Group B) A maximal treadmill exercise test was performed in 25 untreated patients with stable angina and no resting myocardial perfusion defects. R‐wave magnitude increased with exercise in ten patients (+8.2 ± 3%, P < 0.001) and decreased in 16 (‐11.2 ± 3%, P < 0.01). The number of coronary arteries with obstruction greater than 70% was greater for patients in whom the R‐wave magnitude increased with exercise than for patients in whom the R‐wave magnitude decreased (2.1 ± 0.12 vs 1.2 ± 1, P < 0.01). (Group C) In ten patients with coronary artery disease and stable angina in whom R‐wave magnitude decreased before therapy (‐10.0 ± 1.6%, P < 0.01), therapy with propranolol resulted in an increase of postexercise R‐wave magnitude (+7.9 ± 3.2%, P < 0.05). It is concluded that the increase of R‐wave magnitude with exercise may be related to inability of the ischemic myocardium to respond to adrenergic stimulation. Furthermore, changes of R‐wave magnitude cannot be used to diagnose ischemia in patients who are receiving beta‐blocking agents.