This study was undertaken to determine whether patients with unexplained, elevated second-trimester maternal serum human chorionic gonadotropin (hCG) concentrations are at increased risk of adverse pregnancy outcome. In a retrospective study, perinatal outcomes of 355 patients showing elevated second-trimester maternal serum hCG concentrations (> or = 2.0 multiples of median) were compared with those of patients from the same clinic showing normal values (N = 4935), using multiple regression analysis. The effects of variables such as socioeconomic status on pregnancy outcome were taken into account. Between the study subjects and controls, statistically significant differences were observed as regards low birthweight (odds ratio [OR] 1.56, 95% confidence interval [CI]: 1.00-2.44) and intrauterine growth retardation (OR 1.46, 95% CI: 1.03-2.06). Differences in the frequencies of preterm delivery, fetal/perinatal death, fetal distress, or admission to a specific infant care unit were not statistically significant. Preeclampsia (OR 1.76, 95% CI: 1.16-2.70) and velamentous umbilical cord insertion (OR 2.62, 95% CI: 1.47-4.69) were particularly involved in the pathophysiology. Elevated maternal serum hCG concentrations were associated with an increased risk of adverse pregnancy outcome. This resulted mainly from preeclampsia and velamentous umbilical cord insertion. The optimal perinatal management strategy for patients with unexplained elevated hCG levels is not yet resolved. In view of our results, the possibility of preeclampsia and abnormal insertion should be taken into account. In future studies, increased surveillance should be offered in cases showing abnormal uterine artery velocimetric results or abnormal umbilical cord insertion in color Doppler examination to evaluate whether and to what extent intensive monitoring decreases perinatal morbidity in high-risk pregnancies followed because of unexplained, elevated hCG. Until further data are available, no specific recommendations can be made.