The influence of complex plaque morphology on the extent of demand-induced ischemia in unselected patients is not well defined. We sought to investigate the functional significance of lesion morphology in patients who underwent coronary angiography and dobutamine stress echocardiography (DSE). Angiography and DSE were performed within a 6-month period (mean 1 +/- 1 month) in 196 patients. Angiographic assessments involved quantification of stenosis severity, assessment of the extent of jeopardized myocardium, and categorization of plaque morphology according to the Ambrose classification. DSE was interpreted by separate investigators with respect to wall motion score index (WMSI) and number of coronary territories involved. A general linear model was constructed to assess the independent contribution of patient characteristics and angiographic and DSE results with respect to extent of ischemic myocardium. Complex lesion morphology was seen in 62 patients (32%). Patients with complex lesions were more likely to have had prior myocardial infarction (p <0.001) and be current smokers (p = 0.03). During angiography, they exhibited a trend toward a greater number of diseased vessels, had a greater coronary jeopardy score (p <0.001) and more frequent collateral flow (p = 0.03). During echocardiography, patients had a higher stress WMSI (p <0.001) and were more likely to show ischemia in all 3 arterial territories (p <0.01). On multivariate regression, the coronary artery jeopardy score and the presence of complex plaque morphology were independent predictors of the extent of ischemic myocardium (R(2) = 34%, p <0.001). Thus, patients with complex plaque morphology are older, more likely to smoke, and more likely to have had prior myocardial infarction. They exhibit more extensive disease with higher coronary jeopardy scores and a higher resting and peak stress WMSI. Despite these differences, complex plaque morphology remains an independent predictor of the extent of ischemia during stress.