We evaluated the association of hemostatic factors with insulin resistance in relation to reproductive hormones including FSH, estradiol, testosterone, and SHBG. SHBG was used to calculate the free estradiol index and free androgen index. We studied 3,200 women, aged 42-52 yr, in the Study of Women's Health Across the Nation, a prospective multiethnic study of the menopausal transition. We measured the hemostatic factors, fibrinogen, factor VIIc, tissue plasminogen activator (t-PA), and plasminogen activator inhibitor type 1 (PAI-1), as well as glucose and insulin to calculate insulin resistance. After adjustment for body mass index, site, and ethnicity, SHBG was correlated with PAI-1 (partial r = -0.30) and t-PA (partial r = -0.12). Although testosterone was associated with t-PA (partial r = 0.13) and PAI-1 (partial r = 0.07), free androgen index was strongly correlated with t-PA (partial r = 0.18) and PAI-1 (partial r = 0.26). SHBG modified the association of hemostatic factors with insulin resistance. Women with greater insulin resistance had lower SHBG and higher PAI-1. Estrogen measures were not associated with insulin resistance. The influence of sex hormones on hemostatic factors and insulin resistance is poorly understood. SHBG, which influences the amount of bioavailable hormone, significantly modified the association of PAI-1 and t-PA with insulin resistance. The longitudinal Study of Women's Health Across the Nation will help us discern whether this interaction contributes to heart disease and diabetes among postmenopausal women.