Myocardial infarction damages sympathetic nerve fibers coursing through the infarct zone. In this study we investigated whether coronary artery disease without myocardial infarction results in sympathetic denervation. We examined 12 patients without a history of previous myocardial infarction and 19 postinfarction patients. I-123 metaiodobenzylguanidine (MIBG) and technetium-99m sestamibi (MIBI) single-photon emission tomography were conducted at rest to determine the extent of denervated myocardium and the extent of myocardium with reduced perfusion, respectively. In addition, myocardial perfusion during exercise was assessed with MIBI. A MIBG or MIBI defect was determined as being regional uptake of ≤30% of the maximal myocardial activity. All but 1 patient without previous infarction had MIBG defects. MIBG defects (10.3 ± 8.5% of left ventricular mass) were significantly larger than MIBI defects at rest (2.4 ± 3.2%, p <0.001) and during exercise (4.8 ± 6.1%, p <0.05). In multiregression analysis, the size of an MIBG defect was associated with severity of coronary stenoses (≥90% of lumen diameter; p <0.05), but not with age, number of significant stenoses (≥50% of lumen diameter), left main disease, functional class, left venticular ejection fraction, angina pectoris, maximal ST depression, or mean workload during exercise test. MIBG and MIBI defects were significantly larger in patients with severe coronary stenoses than in patients with moderate stenoses (50% to 89% of lumen diameter) (16.4 ± 8.9% vs 6.0 ± 5.2% [p <0.05] and 5.0 ± 3.1% vs 0.6 ± 1.3% [p <0.001], respectively). The size of MIBG (16.1 ± 8.9%) and MIBI defects (7.3 ± 6.5%) at rest in postinfarction patients did not differ from patients with severe stenoses. Our study demonstrates that cardiac adrenergic tissue is very sensitive to ischemia and that regional cardiac sympathetic denervation can occur in patients with stable coronary artery disease without previous myocardial infarction.