Objective: To assess the relationship between maternal corticotropin-releasing; hormone (CRH) levels in second trimester sera, and the risk of preterm delivery in an ethnically heterogeneous sample of pregnant women. Methods: This nested ease-control study included two case groups (97 women who delivered before 35 weeks' gestation, 144 who delivered at 35-36 weeks' gestation), and a control group (244 women who delivered at or after 37 weeks' gestation) frequency matched by ethnicity (black, white) and by alpha-fetoprotein levels (normal, unexplained high). Corticotropin-releasing hormone was evaluated in stored maternal sera collected at 15-19 weeks' gestation from cases and controls. Results: Delivery before 35 weeks' gestation was associated positively with a second trimester, ethnic-specific CRH above 1.5 multiples of the median in white women [odds ratio (OR) 2.3, 95% confidence interval (CI) 1.1, 5.1] and black women (OR 5.0, 95% CI 1.8, 13.3). Sensitivity was 29% in whites and 41% in blacks; specificity was 84% in whites and 80% in blacks. We estimated the positive and negative predictive values to be 6% and 97%, respectively, in white women, and 16% and 93%, respectively, in black women. It was also noted that, within case and control groups, black women had consistently lower CRH levels than white women. Conclusion: Factors that lead to a premature increase in placental CRH production and are associated with an increased risk of preterm birth are evident as early as 15-19 weeks' pregnancy. When considering potential links between stressors, placental changes, CRH levels, and preterm birth, it might be important to stratify or adjust for ethnicity. (Obstet Gynecol 2001;97:657-63. (C) 2001 by The American College of Obstetricians and Gynecologists.).