Background Ischemic ST-segment depression (horizontal or downsloping) is the most common manifestation of exercise-induced myocardial ischemia. The mechanisms responsible for these types of ST-segment depression are largely unknown. We investigated the relation of these 2 types of exercise-induced ST-segment depression to changes in regional myocardial blood flow (RMBF) by using exercise positron emission tomography (PET). Methods and Results The RMBF was measured with nitrogen-13 ammonia PET both at rest and during low-level supine bicycle exercise in 27 patients with angiographically proven coronary artery disease and in 6 healthy volunteers. ST-segment depression was measured from the isoelectric PR segment 80 ms after the J point. Exercise-induced horizontal ST-segment depression ≥0.1 mV was observed in 9 patients and downsloping depression ≥0.1 mV was observed in 18 patients. Multivessel disease was more frequent and areas of exercise-induced ischemia were larger in patients with downsloping depression than in patients with horizontal depression (P < .02, P < .05). In patients with horizontal ST-segment depression, RMBF in ischemic areas and in surrounding areas increased by a similar amount (31% ± 29% and 32% ± 16%) with exercise. In patients with downsloping ST-segment depression, RMBF was unchanged or decreased in ischemic areas (10% ± 24%) but increased in surrounding areas (46% ± 27%) with exercise. In healthy volunteers, RMBF increased in all areas (56% ± 30%) with exercise. Conclusions Compared with horizontal changes in ST-segment morphology, downsloping changes may better indicate severe ischemia and greater differences in the increase of blood flow with exercise in the ischemic myocardium and in the surrounding areas. (Am Heart J 1998;136:533-42.)