Estrogen-progestogen replacement therapy (HRT) may be associated with deterioration of insulin sensitivity in comparison to estrogens alone, which tend to improve insulin sensitivity in postmenopausal women. Insulin sensitivity with the use of continuous combined 17-β estradiol/norethis-terone acetate (E2/NETA) preparations has not been examined before in postmenopausal women. In a double-blind randomized parallel study, we evaluated the effect of 2 mg E2/1 mg NETA (high dose E2/NETA), 1 mg E2/0.5 mg NETA (low dose E2/NETA), or placebo (P) on the insulin sensitivity index (S1) in three groups (18 women/group) of postmenopausal nondiabetic women (follicle stimulating hormone [FSH] > 40 mlU/mL, mean ± SD) aged 56 ± 3 years, BMI 25 ± 4 kg/m2, cholesterol 233 ± 42 mg/dL, and triglycerides 87 ± 36 mg/dL. Insulin sensitivity was measured by means of a two-step hyperinsulinemic euglycemic glucose clamp (insulin infusion rate, 0.25 and 1.0 mU/kg/min for 120 min each) at baseline and after 3 months of daily administration of high dose E2/NETA, low dose E2/NETA, or P. Analysis was performed assuming equivalence of start-end changes of insulin sensitivity among treatment groups (Anderson-Hauck test). S1 was 7.7 ± 2.9,7.5 ± 3.4, 6.8 ± 2.2 at baseline and 6.3 ± 3.0,7.9 ± 2.5, 7.1 ± 3.1 mL/min/m2 per μ, U/mL 3 months after the administration of high dose E2/NETA, low dose E2/NETA, and P, respectively. The low dose E2/NETA group had start-to-end changes of S1 which were equivalent to the P group (0.4 [95% confidence interval [CI] −0.8; 1.7] vs. 0.4 [-0.3; 1.0]) (p = 0.02). For the high dose E2/NETA group, equivalence could not be shown with either the P (p = 0.89) or with the low dose E2/NETA group (p = 0.90). S1 within the high dose E2/NETA group decreased by —1.5 (95% CI −2.7; −0.2) mL/min/m2 per μU/mL. HbA1c decreased from 5.3 ± 0.3 to 5.1 ± 0.3% within the high dose E2/NETA group (p 2 These results indicate that 3 months use of a low dose continuous E2/NETA preparation does not change insulin sensitivity in postmenopausal women. At high dose of E2/NETA, a modest decrease seems possible. The effects of E2/NETA on other parameters of carbohydrate and lipid metabolism are neutral or favorable.