The effect of digoxin on electrocardiogram (ECG) at rest and during exercise, and on QRS amplitude variability (variance ECG) was studied in 20 healthy, middle-aged men and women. Exercise test and variance ECG were performed before and after pretreatment with digoxin orally. Plots of ST-segment level vergus heart rate (HR) were constructed from the rest and exercise ECG recordings. Thus obtained ST/HR loops were compared with loops from 10 male patients with angiographically verified ischemic heart disease (IHD). Pretreatment with digoxin caused a significant (P <.001) ST depression in precordial leads, which was similar in men and women and returned promptly to the isoelectric level after exercise resulting in a counterclockwise rotation of the ST/HR loop. In IHD patients, the exercise-induced ST-segment depression was significantly more pronounced (P <.01) and the ST-segment recovery slower, resulting in clockwise rotated ST/HR loops. The results of variance ECG were not influenced by digoxin. The digoxin-induced ST-reaction during exercise mimics exercise-induced ischemic ST-reaction in patients with IHD, but can still be discerned by the analysis of ST/HR loops.