Cardiac single-photon emission computed tomographic correlates of ST depression were examined in 129 subjects who had inducible ST depression of > or =0.1 mV and reversible perfusion defects. Patients were separated on the basis of single-photon emission computed tomographic defect distribution into a group with anatomically contiguous ischemia (anterior or posterior/inferior defects, n = 68) and a group with anatomically opposed ischemia (anterior and posterior/inferior defects, n = 61). ST depression in the contiguous ischemia group correlated with defect size (r = 0.40, p = 0.001) and severity (r = 0.38, p = 0.002); multivariate regression demonstrated each to be independent determinants of ST-depression magnitude (r = 0.51, p <0.001). In the opposed ischemia group, ST depression did not significantly correlate with defect extent or severity. After adjusting for differences in perfusion indexes, ST depression was paradoxically greater in the contiguous than in the opposed group (2.82 +/- 1.15 vs 2.44 +/- 1.15 mm, p <0.001). In conclusion, these findings demonstrate that the anatomic distribution of ischemia can alter the relation between ST depression and functional indexes of ischemia and may confound the accuracy of assessments of coronary artery disease based on ST-depression magnitude alone.