Context: Preterm birth is associated with maternal cardiovascular risk, but mechanisms are unknown. Objective: We considered that dyslipidemia may predispose women to both conditions and that prepregnancy lipids may be related to preterm birth risk. We hypothesized that low or high prepregnancy plasma lipids would be associated with preterm birth. Design, Setting, and Participants: A total of 1010 women (49% black) enrolled in the multicenter, prospective Coronary Artery Risk Development in Young Adults study with at least one singleton birth during 20 yr of follow-up were evaluated. Main Outcome Measure: Postbaseline preterm births less than 34 wk or 34 to less than 37 wk vs. greater than 37 wk gestation. Results: We detected a U-shaped relationship between prepregnancy cholesterol concentrations and preterm birth risk. Women with prepregnancy cholesterol in the lowest quartile compared with the second quartile (<156 vs. 156-171 mg/dl) had an increased risk for preterm birth 34 to less than 37 wk (odds ratio 1.86; 95% confidence interval 1.10, 3.15) and less than 34 wk (odds ratio 3.04; 1.35, 6.81) independent of race, age, parity, body mass index, hypertension during pregnancy, physical activity, and years from measurement to birth. Prepregnancy cholesterol in the highest quartile (>195 mg/dl) was also associated with preterm birth less than 34 wk among women with normotensive pregnancies (odds ratio 3.80; 95% confidence interval 1.07, 7.57). There were no associations between prepregnancy triglycerides, low-density lipoprotein cholesterol, or high-density lipoprotein cholesterol and preterm birth. Conclusions: Both low and high prepregnancy cholesterol were related to preterm birth risk. These may represent distinct pathways to the heterogeneous outcome of preterm birth. Additional studies are needed to elucidate mechanisms that link low or high cholesterol to preterm birth and later-life sequelae.