Neurodegeneration is one of the most important complications of diabetes mellitus (DM). The exact mechanisms underlying neurodegeneration related to diabetic complications such as cognitive deficits and peripheral neuropathy are not clarified yet. Due to the fact that CCAAT/enhancer binding proteins (C/EBPs) have roles in cognitive functions, memory, synaptic plasticity, inflammation, lipid storage, and response to neurotrophic factors, it is possible to suggest that these transcription factors could have roles in neurodegeneration. Hence, in this study, the effects of experimental diabetes on C/EBPs in the hippocampus, sciatic nerve, and ganglia tissues were examined. After experimentally induced diabetes, immunoreactivity of related proteins was measured by western blotting. C/EBP alpha immunoreactivity in the hippocampus was not altered at 4-weeks but significantly decreased at 12-weeks of diabetes. C/EBP beta immunoreactivity was not altered at 4-weeks whereas significantly increased at 12-weeks of diabetes. In the ganglion, C/EBP alpha immunoreactivity was significantly decreased in diabetes, but C/EBP beta immunoreactivity was not affected. In the sciatic nerve, C/EBP alpha and beta immunoreactivities were significantly decreased in diabetic rats. Furthermore, insulin therapy prevented diabetes-induced alterations in C/EBP alpha and beta immunoreactivities. This study indicated, for the first time, that DM altered the immunoreactivity of C/EBPs in the nervous system. C/EBPs might be one of the important molecular targets which are responsible for neurodegeneration seen in diabetes.