Objective: To compare the prognostic values of unexplained elevated amniotic fluid alpha-fetoprotein (AF AFP ≥ 2.0 multiples of the median [MoM]) and unexplained elevated maternal serum alpha-fetoprotein (MSAFP ≥ 2.5 MoM). Methods: We accessed a data base containing the results of MSAFP screening tests, genetic amniocenteses, and pregnancy outcome data on all women undergoing secondtrimester genetic amniocentesis from October 1988 through August 1994. After excluding all patients whose elevated AFP levels had any identifiable cause (positive AF acetylcholinesterase, AF blood contamination, fetal malformation or aneuploidy, multiple gestation, etc), 5743 cases were analyzed. Relative risks (RR) for selected pregnancy complications were determined. Results: Elevated MSAFP, with any AF AFP, was associated with fetal growth restriction (RR 2.5, 95% confidence interval [CI] 1.4–4.4), stillbirth (RR 3.5, 95% CI 1.4–8.3), preeclampsia (RR 2.8, 95% CI 1.1–7.0), and preterm delivery (RR 2.8, 95% CI 2.3–3.4). Elevated AF AFP, with any MSAFP, was associated with preeclampsia (RR 4.4, 95% CI 2.0–10.0) and preterm delivery (RR 1.7, 95% CI 1.3-2.4). Elevation of both AF AFP and MSAFP was associated with preterm delivery (RR 4.0, 95% CI 2.8–5.7). When elevated AF AFP was found in association with a normal MSAFP, the RR to develop preeclampsia was 4.6 (95% CI 1.9–11.2). Conclusion: Maternal serum alpha-fetoprotein is a better predictor of late pregnancy complications than AF AFP. However, unexplained elevated AF AFP appears to be especially predictive of preeclampsia. © 1996 by The American College of Obstetricians and Gynecologists. Published by Elsevier Science Inc.