Insulin sensitivity as estimated by using the hyperinsulinemic-euglycemic clamp during pregnancy has been related to maternal energy expenditure, fat accretion and fetal growth. To determine whether less time consuming and invasive methods could be employed, we examined whether selected indices of insulin sensitivity derived from an oral glucose tolerance test (IS(OGTT)) or fasting glucose/insulin levels (IS(QUICKI) and IS(HOMA)) can be used to predict insulin sensitivity in women before and during pregnancy. A 2-h euglycemic-hyperinsulinemic clamp (5 mol/L glucose, 40 mU x m(-2) x min (-1) insulin), and 120 min OGTT (75 g load pregravid, 100 g pregnant), was repeated on 15 women [10 with normal glucose tolerance (NGT) and 5 with gestational diabetes mellitus (GDM)], pregravid, and during both early (12-14 weeks) and late (34-36 weeks) pregnancy. An index of insulin sensitivity derived from the clamp (IS(CLAMP)) was obtained from glucose infusion rates adjusted for change in fat free mass and endogenous glucose production measured using [6,6(-2)H2]-glucose. Univariate analysis with combined groups and periods of pregnancy resulted in significant correlations between IS(CLAP) and IS(OGTT), (r2 = .74, P < .0001), IS(QUICKI) (r2 = .64, P < .0001), and IS(HOMA) (r2 = .53, P < .0001). The IS(OGTT) provided a significantly better correlation (P < .0001) than either IS(QUICKI') or IS(HOMA). Multivariate analysis revealed a significant group effect (P < .0003) on the prediction model, and separate equations were developed for the NGT (r2 = .64, P < .0001) and GDM (r2 = .85, P < .0001) groups. When subdivided by period of pregnancy the correlation between IS(CLAMP) and IS(OGTT) pregravid was r = .63, P = .0002, during early pregnancy; r2 = .80, P < .0001 and during late pregnancy; r2 = .64, P = .0002. The IS(OGTT) provides an excellent means of estimating maternal insulin sensitivity during pregnancy. The information obtained from the IS(OGTT) will be useful in making clinical decisions on maternal care and facilitating optimal pregnancy outcome.