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OBJECTIVES: To assess the long-term effects of 4 years of menopausal hormone therapy (mHT) on the brain's white matter architecture in women who initiated mHT within 3 years of menopause onset. METHODS: The Kronos Early Estrogen Prevention Study (KEEPS) was a multicenter, double-blind, randomized, placebo-controlled 4-year mHT trial with treatment arms of oral conjugated equine estrogens (oCEE), transdermal 17β-estradiol (tE2), and placebo in recently postmenopausal women. KEEPS Continuation was an observational follow-up of KEEPS participants. White matter integrity was evaluated in KEEPS Continuation participants 10 years after KEEPS completion using white matter hyperintensity volume, diffusion magnetic resonance imaging (dMRI) techniques, and cerebral infarcts. Linear regression models were fitted for each brain region to evaluate if there were differences in white matter between KEEPS treatment arms. RESULTS: There was no evidence to suggest the long-term effects of 4 years of mHT on brain white matter in KEEPS Continuation participants [n=266, mean age 67 (58-73)]. No differences in dMRI metrics were found in each of the treatment arms (oCEE n=70; tE2 n=79) when compared to placebo (n=94), following a false discovery rate adjustment for multiple comparisons. There were no statistically significant differences in white matter hyperintensity volume or infarct occurrence when comparing each of the treatment arms to placebo. CONCLUSIONS: We found no evidence of the long-term effect of 4-year mHT on white matter integrity when compared to placebo, consistent with emerging evidence of the safety of short-term use of mHT in recently postmenopausal women.