Objective: The purpose of this study was to determine whether mid-trimester insulin resistance is associated with subsequent preeclampsia. Study Design: This was a secondary analysis of 10,154 nulliparous women who received vitamin C and E or placebo daily from 9-16 weeks gestation until delivery. Of these, 1187 women had fasting plasma glucose and insulin tested between 22 and 26 weeks gestation. Insulin resistance was calculated by the homeostasis model assessment of insulin resistance (HOMA-IR) and the quantitative insulin sensitivity check index. Results: Obese women were twice as likely to have a HOMA-IR result of <75th percentile. Hispanic and African American women had a higher percentage at <75th percentile for HOMA-IR than white women (42.2%, 27.2%, and 16.9%, respectively; P < .001). A HOMA-IR result of <75th percentile was higher among the 85 nulliparous women who subsequently had preeclampsia, compared with women who remained normotensive (40.5% vs 24.8%; adjusted odds ratio, 1.9; 95% confidence interval, 1.13.2). Quantitative insulin sensitivity check index results were similar to the HOMA-IR results. Conclusion: Midtrimester maternal insulin resistance is associated with subsequent preeclampsia. © 2011 Mosby, Inc.