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The aim of the study was to explore the therapeutic potential of menopausal hormone therapy (MHT) in women with mild cognitive impairment (MCI).Thirty-seven postmenopausal women (age range: 57-82 y) with multiple-domain, amnestic subtype MCI were randomly assigned to either placebo (n = 18) or MHT (n = 19) for 24 months (percutaneous estradiol [E2] gel [0.1%, 2 mg/d] and oral micronized progesterone [MP4] [100 mg/d]). All participants received donepezil, and apolipoprotein E genotype was determined. The primary endpoint was general cognitive function: Alzheimer's disease Assessment Scale, cognitive subscale, the Korean version of Mini-Mental State Examination (K-MMSE), and the Korean version of the Montreal Cognitive Assessment (MoCA_K) were performed in-person every 6 months.Twenty-one participants (placebo 13, MHT 8) completed the trial (56.8%). Progression rates to dementia were 52.9% (9/17) in the placebo group and 44.4% (8/18) in the MHT group. Within-group analysis showed that all three tests significantly worsened during the trial in the placebo, but not the MHT groups. Analysis adjusted for ε4 allele demonstrated that MHT significantly reduced deterioration of MoCA_K score, a sensitive tool for assessing global cognition in MCI (P = 0.0261). Compared with the control group, both MoCA_K (P = 0.043; mean difference, 3.85; 95% CI, −0.46 to 8.16) and K-MMSE (P = 0.0319; mean difference, 3.26; 95% CI, 0.04-6.48) scores were significantly better at 24 months in the MHT group.Long-term MHT using percutaneous E2 gel and oral MP4 might attenuate cognitive decline in postmenopausal women with MCI.