Impaired fasting glucose (IFG) is more prevalent in men and impaired glucose tolerance (IGT) more prevalent in women. To explore whether this sex difference is related to female sex hormones, we performed a cross-sectional analysis of data from 2,164 (1,329 women and 835 men) first-degree relatives of individuals with type 2 diabetes. Subjects were categorized based on a 75-g oral glucose tolerance test. Sex and hormone replacement therapy (HRT) effects on the distribution of glucose tolerance were assessed using multinomial logistic regression corrected for familial clustering. Compared with men, women were more likely to have isolated IGT (relative risk 1.8 [95% CI 1.3-2.5]) and less likely to have isolated IFG (0.5 [0.3-0.7]) adjusted for ethnicity, age, waist, fasting insulin, and early insulin release (DeltaI(0-30)/DeltaG(0-30)). To evaluate HRT effects, postmenopausal women using (n = 238) or not using (n = 378) HRT were compared. HRT users were more likely to have isolated IGT (2.2 [1.2-4.0]) after adjustment, but the prevalence of isolated IFG did not differ by HRT status. Based on the influence of sex and HRT on the prevalence of isolated IFG and isolated IGT, we conclude that female sex hormones may play an important role in the pathogenesis of IFG and IGT.