Aim: To study the effects of long-term, low-dose sex hormone replacement therapy (HRT) on the volume and biochemical changes of the hippocampus in postmeno-pausal women carrying apolipoprotein E (apoE) gene ε3 or ε4. Methods: Eighty-three postmenopausal women who had used a low dose of HRT for over 4 years were selected as the HRT group, and 99 postmenopausal women with matched age and education were enrolled as the control group. ApoE alleles were analyzed by PCR. Magnetic resonance imaging was performed to determine the volume of the brain hippocampus. Proton magnetic resonance spectroscopy was used to detect the biochemical changes in the anterior cingulate cortex and hippocampus in apoE ε4 and ε3 carriers. Six common cognitive tests were used to make an overall evaluation of cognitive function. Results: Analysis with the apoE ε4 carriers showed that the volume of the hippocampus of the control group were significantly lower than those of the HRT group. The biochemical analysis showed that there was an increase of N-acetylaspartate (NAA)/total creatine (tCr) and a decrease of myoinositol (mI)/tCr in the hippocampus of apoE ε4 carriers in the HRT group, compared with the control group. For the apoE ε3 carriers, the least squares means (LSMEAN) of the HRT group was higher than that of the control group. Conclusion: This study showed that long-term, low dose HRT might be beneficial for reducing the risk of AD development in vulnerable postmenopausal women. Meanwhile, HRT could increase the LSMEAN of apoE ε3 carriers.