Objectives: To evaluate the effect of transdermal 17-beta-estradiol (50 mu g/day) on glucose metabolism of postmenopausal women. Study design: A frequently sampled intravenous glucose tolerance test (FSIGT), to calculate insulin sensitivity (S-I) and peripheral glucose utilization independent of insulin (S-G), and an oral glucose tolerance test (75 g; OGTT), were performed in nine postmenopausal women prior to, and after 2 months of, treatment. Results: Estradiol decreased insulin and increased the C-peptide/insulin ratio both during fasting (P < 0.02) and OGTT (insulin levels, P < 0.01; C-peptide/insulin ratio, P < 0.05), but not FSIGT. Glucose levels, C-peptide levels, S-I and S-G were not affected. Conclusions: In spite of unmodified S-I, the reduction of insulin levels and the increase of the C-peptide/insulin ratio, observed during fasting and OGTT, support a beneficial effect of estradiol on glucose metabolism. This effect probably requires the interplay of estradiol with gastrointestinal factors. (C) 1997 Elsevier Science Ireland Ltd.