ABSTRACT—Altered angiogenesis and insulin resistance, which are intimately related at a molecular level, characterize preeclampsia. To test if an epidemiological interaction exists between these two alterations, we performed a nested case-control study of 28 women who developed preeclampsia and 57 contemporaneous controls. Serum samples at 12 weeks of gestation were measured for sex hormone binding globulin (SHBG; low levels correlate with insulin resistance) and placental growth factor (PlGF; a proangiogenic molecule). Compared with controls, women who developed preeclampsia had lower serum levels of SHBG (208±116 versus 256±101 nmol/L, P =0.05) and PlGF (16±14 versus 67±150 pg/mL, P <0.001), and in multivariable analysis, women with serum levels of PlGF ≤20 pg/mL had an increased risk of developing preeclampsia (odds ratio OR 7.6, 95% CI 1.4 to 38.4). Stratified by levels of serum SHBG (≤175 versus >175 mg/dL), women with low levels of SHBG and PlGF had a 25.5-fold increased risk of developing preeclampsia (P =0.10), compared with 1.8 (P =0.38) among women with high levels of SHBG and low levels of PlGF. Formal testing for interaction (PlGF×SHBG) was significant (P =0.02). In a model with 3 (n−1) interaction terms (high PlGF and high SHBG, reference), the risk for developing preeclampsia was as followslow PlGF and low SHBG, OR 15.1, 95% CI 1.7 to 134.9; high PlGF and low SHBG, OR 4.1, 95% CI 0.45 to 38.2; low PlGF and high SHBG, OR 8.7, 95% CI 1.2 to 60.3. Altered angiogenesis and insulin resistance are additive insults that lead to preeclampsia.