In both humans and animal models, diabetic sympathetic autonomic neuropathy is associated with the selective development of markedly enlarged distal axons and nerve terminals (neuroaxonal dystrophy, NAD). NAD occurs in the prevertebral superior mesenteric and celiac ganglia (SMG-CG), but not in the paravertebral superior cervical ganglion (SCG). To identify molecular differences between these ganglia that may explain their selective vulnerability to NAD, we have examined global gene expression patterns in control and diabetic rat sympathetic ganglia before and after the onset of structural evidence of NAD. As predicted, major differences in transcriptional profiles exist between SCG and SMG-CG in normal young adult animals including, but not limited to, known differences in neurotransmitter-related gene expression. Gene expression patterns of diabetic SMG-CG and SCG, prior to the development of NAD lesions, also differ from their age-matched non-diabetic counterparts. However, diabetes has ganglion-specific effects on gene expression; of approximately 110 transcripts that were differentially expressed between diabetic and control sympathetic ganglia, only 5 were differentially expressed as a result of diabetes in both SCG and SMG-CG. Genes involving synapse and mitochondrial structure and function, oxidative stress, and glycolysis were highly represented in the differentially expressed gene set. Differences in the number of synapse-related gene alterations in diabetic SMG-CG (18 genes) versus SCG (2 genes) prior to the onset of NAD may also well explain the selective development of NAD in the SMG-CG. These results provide support for the specificity of diabetes-modulated gene expression for selected neuronal subpopulations of sympathetic noradrenergic neurons.