This study was undertaken to determine whether positron emission tomography (PET) performed after the intravenous injection of 11C-palmitate permits differentiation of patients with ischemic from those with nonischemic dilated cardiomyopathy. PET was performed after intravenous injection of 11C-palmitate in 10 patients with ischemic and in 10 with nonischemic dilated cardiomyopathy. Regions of homogeneously severely depressed accumulation of 11C-palmitate, representing 15% or more of the expected myocardial cross-sectional area, were observed in 8 of 10 patients with ischemic but in none of 10 patients with nonischemic cardiomyopathy. Patients with nonischemic cardiomyopathy had marked spatial heterogeneity of the accumulation of palmitate throughout the left ventricular myocardium, whereas most tomographic sections from patients with ischemic cardiomyopathy accumulated 11C-palmitate more homogeneously in regions exclusive of discrete defects indicative of remote infarction. Thus, a larger number of discrete noncontiguous regions (17 ± 5 compared with 12 ± 4, p < 0.001) and greater reduction of average 11C-palmitate content (59 ± 6 compared with 64 ± 10% maximal myocardial radioactivity, p < 0.05) were seen in the tomographic reconstructions from patients with nonischemic than in those from patients with ischemic cardiomyopathy. These findings support the hypothesis that multiple myocardial infarctions underlie the process seen as dilated cardiomyopathy in patients with coronary artery disease. Our findings indicate that PET permits differentiation of patients with ischemic from those with nonischemic cardiomyopathy.