The effect of antianginal therapy on the incidence of an early positive exercise response as a screening tool for 3-vessel and left main (LM) coronary artery disease (CAD) was examined. Fifty-seven men with stable angina pectoris underwent bicycle ergometry before and after long-acting nitrate or calcium antagonist therapy was instituted. An early positive response was defined as signs of myocardial ischemia at low levels of myocardial and total body workload (corresponding to a workload of less than 300 kpm/min). Thirty-nine patients (68%) had an early positive response before therapy, compared with 14 (24%) after therapy. Of 24 patients undergoing coronary angiography, 12 had 3-vessel CAD (including 2 with LM), 5 had 2-vessel CAD, 6 had 1-vessel CAD and 1 patient had no CAD. The sensitivity and specificity of an early positive response in predicting 3-vessel/LM CAD changed from 92% and 58% before to 42% and 75% after therapy. The positive and negative predictive values changed from 69% and 88% before to 63% and 63% after therapy. It is concluded that antianginal therapy reduces the value of an exercise test as a screening tool for 3-vessel/LM CAD.