Emerging evidence has demonstrated the neuroprotection of estrogen in Alzheimer's disease (AD). The hippocampus, an important target of estrogen action, is severely affected in the Alzheimer process. The aim of present study was to detect the distribution of estrogen receptor-alpha (ER-alpha) and the relationship between ER-alpha-containing neurons and the pretangles stained by Alz-50 in the hippocampus of AD patients. The results showed that more than half of hippocampal neurons expressed ER-alpha. The number of cytoplasmic ER-alpha-positive neurons was significantly decreased in the CA1 and CA2 subfields of AD hippocampus, but the ratio of these ER-alpha-expressing neurons to the nucleolated neuronal profiles stained by thionin was not different between the two groups. Interestingly, the number of nuclear ER-alpha-staining neurons was also markedly decreased in the CA1 and CA2 subfields of AD hippocampus, and the percentage of these nuclear staining neurons was also significantly decreased in the same subfields. Furthermore, some double-labeled neurons containing ER-alpha and Alz-50 were found in AD patients. However, in these double-labeled neurons, ER-alpha was only located in the cytoplasm. Thus, we hypothesize that the nuclear ER-alpha may play more important roles of neuroprotection during the process of AD.