We reported that the integral membrane 2B gene (ITM2B, also called BRI2) is a target of BCL6 repression in lymphomas. Molecular alterations in ITM2B are associated with 2 neurodegenerative diseases, Familial British and Danish dementia, and dysregulation of ITM2B function has been implicated in the pathogenesis of Alzheimer disease (AD). Although ITM2B expression has been studied, the distribution of BCL6 in human brain has not been described. Our goal is to analyze BCL6 and ITM2B localization in normal human brains and in AD by immunohistochemistry to understand their relationship. We found that, in general, they have a reciprocal relationship. BCL6 expression is present in isolated cortical neurons, granule cells in the cerebellum, scattered glial cells, and in some cells of the ependyma and choroid plexus. ITM2B is expressed in most cortical neurons, neurons of the hippocampus and dentate nucleus, cerebellar Purkinje and granule cells, and (newly described here) in focal neurons in the basal ganglia, many neurons of the thalamus and brainstem, many cells in the ependyma and choroid plexus, and in the smooth muscle of blood vessels. ITM2B expression is prominent in plaques in AD-containing dystrophic neurites but absent in neurofibrillary tangles; BCL6 expression is absent in neurofibrillary tangles and in the nuclei of cells associated with plaques in AD. It is essential to understand the localization of BCL6 and ITM2B in the brain before considering manipulation of their expression as a potential therapeutic tool.