OBJECTIVE To evaluate the clinical significance of a second-trimester elevated maternal serum hCG in women carrying singleton, chromosomally normal fetuses. METHODS The results of second-trimester maternal serum screening (alpha-fetoprotein [MSAFP], hCG, and unconjugated estriol) for 25,438 women were reviewed, and those with hCG values exceeding 3.0 multiples of the median (MoM) were identified. A control population was selected only on the basis of samples accessioned by the laboratory at the same time as the study group. Follow-up information was collected from physicians' offices for both groups. Incidence of fetal or neonatal loss (spontaneous abortion, fetal death, and neonatal death combined), preterm birth (before 37 weeks' gestation), small for gestational age, and preeclampsia were compared. RESULTS Three hundred twenty-two women (1.3%) had hCG levels exceeding 3.0 MoM. In addition to chromosomal abnormalities and fetal death at the time of testing, this group showed a significantly higher incidence of fetal or neonatal death, preterm birth, low birth weight, and preeclampsia than did controls. For patients with elevated second-trimester hCG, many of the preterm deliveries occurred before 34 weeks' gestation. Logistic regression analysis indicated that hCG, MSAFP, and race were significant independent factors in predicting risk for adverse outcome. CONCLUSIONS Similar to elevated AFP, elevated hCG is associated with poor pregnancy outcome. By combining the results of the two tests, it may be possible to improve substantially the identification of patients at very high risk for adverse outcomes.