Postmenopausal hormone replacement therapy (HRT) protects women from the risk of cardiovascular system disease, osteoporosis, and dementia. There are conflicting reports about the effects of HRT on insulin resistance. The purpose of this study was to investigate the effects of HRT on insulin resistance with the hyperinsulinemic euglycemic clamp technique, the most sensitive technique measuring insulin resistance. Conjugated estrogen (0.625 mg/d) and medroxyprogesterone acetate (5 mg/d) were given to 15 postmenopausal women with insulin resistance. After 3 mo of HRT, the M value (total glucose consumption) increased 28 % (p < 0.001), low-density lipoprotein (LDL) cholesterol decreased 12.9% (p < 0.044), high-density lipoprotein (HDL) cholesterol increased 17% (p < 0.009), total cholesterol decreased 9.1 % (p < 0.016), and serum insulin decreased 33% (p < 0.022) compared to baseline values before HRT was started. No significant changes in glucose, C-peptide, and triglyceride levels were observed. Whereas there were no differences regarding glucose, total cholesterol, LDL cholesterol, HDL cholesterol, and triglyceride levels between the insulin-resistant (n = 15) and non-insulin-resistant women (n = 24) (p > 0.05), there were significant differences in M value, insulin, and C-peptide levels between these groups (p < 0.05). We believe that HRT with this combination may protect postmenopausal women from coronary artery disease (CAD) through its beneficial effects on insulin resistance, hyperinsulinemia, and lipid levels, which are considered to be important factors in CAD pathogenesis.