The degradation of aberrantly phosphorylated tau in neurons plays an important role in the pathogenesis of Alzheimer's disease (AD). hHrd1 is a newly identified ubiquitin ligase involved in the endoplasmic reticulum (ER)-associated protein degradation. The expression and function of hHrd1 in AD brain remains elusive. In the present study, the expression of hHrd1 in AD hippocampus and the morphological relations between hHrd1 expression and pretangle formation were studied by using immunohistochemical single- and double-labeling methods. The results showed that hHrd1 was expressed in neurons and reactive astrocytes, especially in the CA2-CA4 hippocampal subfields. The ratio of hHrd1-positive neurons/astrocytes to total neurons/astrocytes was increased in the CA1 subfield in AD hippocampus compared with the age-matched controls (P < 0.05). Most Alz-50 labeled pretangles were colocalized with hHrd1, and the expression levels showed an inversed change, implied that hHrd1 might be associated with the degradation of hyperphosphorylated tau.