Objective: Heart fat depots, within [epicardial adipose tissue (EAT)] and outside [paracardial adipose tissue (PAT)] the pericardium, have been linked to carotid atherosclerosis in various populations. Postmenopausal women have greater volumes of heart fat than premenopausal women. Our previous work suggests that lower endogenous estrogen may contribute to heart fat accumulation, although possibly limited to PAT, while postmenopausal oral hormone therapy (HT) may slow its progression. We evaluated the effect modification of HT use over 48 months on associations between heart fat accumulation and carotid artery intima-media thickness (CIMT) progression in recently postmenopausal women. Methods: The Kronos Early Estrogen Prevention Study (KEEPS) was a multi-center, randomized, double-blind placebo-controlled trial to investigate effects over 48 months of oral conjugated equine estrogens (o-CEE) and transdermal 17β-estradiol (t-E2), both given with cyclic progesterone, compared to placebo, on progression of CIMT in recently postmenopausal women. EAT and PAT volumes, and CIMT were measured at baseline and at 48 months. Associations between the absolute changes in heart fat volumes and CIMT as well as effect modification by HT type were tested using linear regression, adjusting for age, race, study site, employment status, diastolic and systolic blood pressure, anti-hypertensive medications, insulin resistance index, lipids, body-mass index, smoking, alcohol consumption, C-reactive protein, and adipokines. Results: Of 727 randomly assigned women, 467 [mean age (SD): 52.7(2.5); 78.2% Caucasian] had heart fat volumes and CIMT measured at both time points. Overall, changes in EAT and PAT were not associated with CIMT progression; however, assigned treatment significantly modified the association between changes in PAT, but not EAT, and CIMT progression in unadjusted model, P=0.04. In o-CEE group, CIMT progression was 0.028mm (SE:0.01mm) lower, per 1 unit increase in log PAT, than in t-E2 group, P=0.01, and trended 0.017mm (SE:0.01mm) lower than in placebo group, P=0.09. Although adjusted analysis attenuated these findings (P-value for interaction 0.09), differences between o-CEE and t-E2 groups remained significant, P=0.03. Conclusion: HT use modified the association between PAT accumulation, but not EAT, and CIMT progression. Our results suggest a potential beneficial impact of o-CEE (but not transdermal E2) on the relationship between adverse changes in PAT and CIMT. The current findings support the notion that EAT and PAT are distinct fat depots and suggest a complex role of HT in the association between heart fat and CIMT progression in recently postmenopausal women.