•Menopausal hormone therapy had beneficial impact on carotid artery wall composition assessed by gray scale median in postmenopausal women free from CVD. To evaluate the effect of hormone therapy (HT) on arterial wall composition by ultrasound. The effect of HT on the progression of subclinical atherosclerosis has been well-described using measurements of common carotid artery (CCA) wall thickness. However, it is unknown whether the change in arterial wall anatomic structure is accompanied by an effect of HT on arterial wall composition. A total of 643 healthy postmenopausal women divided into two strata according to the time since menopause (<6 years, the early-postmenopause group; or >10 years, the late-postmenopause group) were randomized to receive either active treatment or placebo. For hysterectomized women, the active treatment was oral micronized 17β-estradiol 1 mg/day; for women with a uterus, 4% vaginal micronized progesterone gel 45 mg/day for 10 days each month was added to the estradiol regimen. Gray-scale median of the CCA intima-media complex (IM-GSM), a (unitless) measurement of arterial wall composition based on echogenicity, was determined by high-resolution B-mode ultrasonography. Lower IM-GSM, or less echogenicity, indicates more atherosclerosis. IM-GSM and serum estradiol (E2) concentration were assessed every 6 months over a median 4.8-year trial period. Linear mixed effects regression models were used for all analyses. Overall, IM-GSM progression/year had a negative trajectory, reflecting reduction in echogenicity over time (worsening atherosclerosis). HT effects on IM-GSM progression/year differed by postmenopause strata (interaction p-value = 0.02). IM-GSM progression/year (95% CI) in the early postmenopause group randomized to HT was −0.50 (−0.82, −0.18)/year compared with −1.47 (−1.81, −1.13)/year among those randomized to placebo (p-value <0.0001). In the late postmenopause group, the annual IM-GSM progression rate did not significantly differ between HT and placebo (p = 0.28). Higher mean on-trial E2 (pg/ml) levels were associated with higher IM-GSM progression, indicating less atherosclerosis progression in all women (β (95% CI) = 0.006 (0.0003, 0.01), p = 0.04). For each pg/dl E2, IM-GSM progression/year was 0.007 ((−0.0002, 0.01), p = 0.056) in the early and 0.003 ((−0.006, 0.01), p = 0.50) in the late postmenopause group (interaction p-value = 0.51). CIMT progression rate (μm/year) was significantly inversely associated with the IM-GSM progression (β (95% CI) = −4.63 (−5.6, −3.7), p < 0.001). HT, primarily with oral estradiol, reduced atherogenic progression of arterial wall composition in healthy postmenopausal women who were within 6 years from menopause. Trial registration number: NCT01553084