Amyloid-β (Aβ) peptide, a cleavage product of the amyloid-β protein precursor (AβPP), has been reported to be detected in the intracellular compartment. Most studies reporting the presence of intracellular Aβ are based on the use of immunohistochemistry. In this study, the presence of AβPP and Aβ was assessed by applying immunohistochemistry in postmortem human brain tissue samples obtained from 10 neurologically intact subjects, the youngest being 2 years of age, one aged with mild cognitive impairment, 14 neurologically diseased, and in one brain biopsy sample obtained from a subject with normal pressure hydrocephalus. Intracellular immunoreactivity was detected in all ages independent of the disease state or existence of extracellular Aβ aggregates with all antibodies directed to AβPP, with three Aβ antibodies (4G8, 6E10, and 82E1), clones that are unable to distinguish Aβ from AβPP. These results suggest that it is AβPP rather than Aβ that is detected intracellularly when using the antibodies listed above. Furthermore, the staining results varied when different pretreatment strategies were applied. Interestingly intracellular Aβ was detected with antibodies directed to the C-terminus of Aβ (neoepitope) in subjects with Alzheimer's disease. The lack of intracellular immunoreactivity in unimpaired subjects, when using antibodies against neoepitopes, may be due to a lack or a low level of the protein that is thus undetectable at light microscopic level by immunohistochemistry method. The staining results and conclusions depended strongly on the chosen antibody and the pretreatment strategy and thus multiple antibodies must be used when assessing the intracellular accumulation of Aβ.