Scintigraphy using I-123-metaiodobenzylguanidine (I-123-MIBG) and Tc-99m-methoxyisobutylisonitrile (Tc-99m-MIBI) allows assessment of the cardiac sympathetic innervation and the myocardial perfusion. To investigate the natural history of cardiac sympathetic denervation in long-term diabetic patients without myocardial perfusion defects, global and regional I-123-MIBG and Tc-99m-MIBI uptake was determined (score 1-6; 1 = normal uptake, 6 = no uptake) in 22 patients with insulin-dependent (type I) diabetes mellitus (IDDM) at 3-year follow-up. All patients were treated with intensive insulin therapy and HbA1c was 8.0% +/- 1.0% at entry compared with 7.9% +/- 1.1% at follow-up. Cardiac sympathetic denervation (I-123-MIBG uptake score > 2), initially observed in 18 patients, was detectable in 21 patients at follow-up. The global myocardial I-123-MIBG uptake score deteriorated in eight patients, remained unchanged in 11 and improved in three patients. The changes in mean global I-123-MIBG uptake score (3.5 +/- 1.0 versus 3.8 +/- 0.8) were not significant. Reduction of the anterior, lateral, posterior, septal, and apical I-123-MIBG uptake did not progress significantly during follow-up. The mean uptake score of the posterior myocardial region (4.7 +/- 0.8) was smaller than the uptake score of the anterior (3.0 +/- 1.1, p = 0.001), lateral (3.2 +/- 0.9, p < 0.001) and septal (4.1 +/- 1.1, p < 0.05) myocardial regions. At follow-up, moderate myocardial perfusion defects (global Tc-99m-MIBI uptake score = 3) were detectable in four patients. Our study demonstrates that scintigraphically assessed cardiac sympathetic denervation does neither significantly regress nor progress on the average in a group of long-term IDDM patients during a 3-year follow-up. Thus, it is concluded that cardiac sympathetic abnormalities are a persistent, yet frequent phenomenon in long-term IDDM patients.