The neuropathologic alterations which underlie autonomic nervous system dysfunction in aging and in a variety of diseases have been systematically examined in the sympathetic ganglia of a series of 347 autopsied adults and in a review of previously published studies. Markedly swollen terminal axons containing neurofilamentous aggregates were found immediately adjacent to the neuronal cell bodies of prevertebral sympathetic ganglia in aging, in diabetes, and, to a lesser extent, in alcoholism. Dystrophic axons appeared to involve subpopulations of intraganglionic nerve fibers, chiefly those containing neuropeptide Y (NPY), and were more frequent in males than females. Neither aging nor diabetes resulted in significant numbers of actively degenerating neurons or a substantial decrease in neuronal density. Parenchymal aggregates of lymphocytes in the ganglionic neuropil and perivascular regions represented a frequent histologic finding in both prevertebral and paravertebral ganglia; however, they were not selectively increased in frequency or intensity in diabetic subjects or in any other disease entity. Many dilated clear "vacuoles," apparently located within the neuronal cell bodies of paravertebral and prevertebral ganglia according to light microscopy, were subsequently shown by electron microscopy to represent vacuolated or fluid-filled neurites, most likely terminal axons or synapses. Vacuolated neurites were more frequent in, although not confined to, diabetic patients. Similar pathologic findings have been reported in studies of sympathetic ganglia in various human diseases. The frequency of some pathologic lesions in control populations as a function of age or gender necessitates the careful selection of a relatively large, appropriately matched, control population for comparison with presumed disease-induced ganglionic neuropathology, and emphasizes the importance of quantitative comparisons.