OBJECTIVE: Intra-abdominal fat (IAF) accumulates with age, is greater among postmenopausal vs. premenopausal women, and is linked to risk for both type 2 diabetes and cardiovascular disease. Whether hormone replacement therapy (HRT) prevents or attenuates changes in IAF and related risk factors is not clear. The objectives of this observational study were to 1) determine whether HRT attenuated the expected age-related increase in IAF and 2) identify the independent effects of HRT and fat distribution on changes in disease risk factors. RESEARCH METHODS AND PROCEDURES: Subjects were early postmenopausal white women 45 to 55 years of age. Women either used HRT at the time of enrollment (n = 33) or did not (n = 17). Subjects were evaluated at baseline and 2 years for body composition (DXA), body fat distribution (computed tomography), insulin sensitivity (Si; minimal model), and serum lipids. RESULTS: IAF increased significantly over 2 years, and this increase was not attenuated by HRT. HRT users had less IAF throughout the study. HRT users showed an increase in Si, whereas non-users showed a decrease. Superficial subcutaneous adipose tissue was significantly and independently related to total cholesterol, whereas IAF was related to high-density lipoprotein cholesterol, triglycerides, and Si. DISCUSSION: HRT users had less IAF at baseline and throughout the study. Whether HRT altered the relationship between total body fat and IAF or whether differences between groups existed before the study should be addressed through a randomized, interventional study design. HRT had a significant effect on Si; IAF and superficial subcutaneous adipose tissue were significant determinants of disease risk factors.