To determine if cardiac autonomic neuropathy (CAN) contributes to diabetic cardiomyopathy, left ventricular function was assessed by resting and exercise radionuclide ventriculography (RVG) in 30 patients with long-standing insulin-dependent diabetes mellitus who had no clinical, electrocardiographic, or tomographic thallium scan evidence of heart disease. In 11 of 30 patients (37%), RVG revealed abnormal left ventricular performance. CAN was found in 91% of these patients. RVG was abnormal in 59% of patients with CAN and in only 8% of patients without CAN (P less than 0.005). There were significant reductions in mean (+/- SE) ejection fractions (EF) in patients with CAN at rest (62.8 +/- 2.2% vs. 75.2 +/- 2.5%; P less than 0.001) and with maximal exercise (65.8 +/- 2.6% vs. 80.9 +/- 2.3%; P less than 0.001) compared to patients without CAN. There was an inverse correlation between the autonomic function score and both resting EF (r = -0.53; P less than 0.002) and exercise EF (r = -0.55; P less than 0.002). Systolic function did not correlate with age, sex, duration or control of diabetes, microvascular complications, or plasma norepinephrine levels. Thus, approximately one third of our study population had evidence for depressed left ventricular function in the absence of ischemic heart disease, and the cardiac dysfunction was related to the severity of CAN. CAN may be a contributor to cardiac dysfunction in diabetes mellitus.