The effect of hypoglycemia on the brain has been well documented over the past several decades, most of which include essentially grey matter changes such as neuronal loss and gliosis. What is known about white matter changes in hypoglycemia is mostly documented through medical imaging, while very few articles describe the histopatholgical and immunohistochemical findings. In this study we report a 65-year-old lady with history of type II diabetes mellitus since the age of 45, and multiple hypoglycemic episodes in which her presentations fluctuated clinically between unusual behavior, stupor and coma. Her MRI revealed a small hyperintensity in the splenium of the corpus callosum. The episodes started three months prior to her death. Screening for infective, ischemic, traumatic and other metabolic causes for her symptoms was negative. She underwent autopsy. Histologic examination of selected sections of her brain showed no evidence of any ischemic changes. The splenium of the corpus callosum, the internal capsule and the bilateral occipital subcortical white matter, showed evidence of subacute axonal degeneration that was confirmed by beta-amyloid precursor protein and neurofilament protein. It is important to recognize hypoglycemia per se as a cause of neuroaxonal degeneration. The histological features supporting this diagnosis have been reviewed, along with the special and immunohistochemical staining of this particular abnormality.