Objective: To examine cross-sectionally the influence of hormone replacement therapy (HRT) on the relationship between body composition and insulin sensitivity (Si). Research Methods and Procedures: Subjects were 57 early postmenopausal white women, 33 receiving HRT and 24 controls. Body composition was estimated using DXA and computed tomography scans at the abdomen and mid-thigh. Si was assessed by a frequently sampled intravenous glucose tolerance test with minimal model analysis. Results: Compared with nonusers, HRT users had lower visceral adipose tissue, fasting serum glucose, and fasting insulin. Total body fat and unadjusted Si did not differ between groups. Visceral adipose tissue mass (VATM) was the only body-fat compartment significantly associated with Si (r2 = 0.43, p < 0.0001) in a model including total-body fat, upper-trunk fat, subcutaneous abdominal fat mass, leg fat, and mid-thigh low-density lean tissue. Lean body mass was positively correlated with Si among HRT users and tended to be negatively correlated among nonusers. HRT status also affected the relationship between VATM and Si such that, relative to nonusers, HRT users had lower Si across lower VATM levels, but higher Si across higher VATM. Discussion: These results suggest that in postmenopausal women, VATM is uniquely related to Si. HRT affects the relationship between VATM and Si and between lean body mass and Si. These interactions should be considered in future studies.