The purpose of the present study was to document that the coronary collateral vessels do not open immediately upon the occurrence of myocardial ischemia. A multistage bicycle exercise was performed to determine a maximal tolerable work load until the onset of angina and significant ST segment depression in 10 patients with well-developed collateral circulation. On a different day, exercise with the maximal tolerable work load was repeated for a comparable exercise duration. In 2 of the 10 patients, anginal pain was gradually alleviated despite the continuation of exercise with fixed work load. The extent of ST segment depression at 3 min of exercise with fixed work load was 0.20 ± 0.10 (SD) mV, significantly (p < 0.05) greater than 0.16 ± 0.08 mV at the end of exercise with fixed work load. In contrast, the rate-pressure product was smaller at 3 min than at the end of exercise with fixed work load (20,900 ± 5,500 vs. 22,700 ± 5,700 mm Hg · beats/min; p < 0.05). In 5 patients without well-developed collateral circulation, the extent of ST depression changed in parallel with changes in rate-pressure product during exercise with fixed work load. Thus, it is concluded that the delayed collateral opening plays a critical role in the pathogenesis of myocardial ischemia in patients with a totally occluded coronary artery.