An index case of "undetectable" maternal serum alpha-fetoprotein at 16 weeks in the first pregnancy of a 28-year-old woman was associated with birth of an infant with trisomy 18. This fortuitous finding stimulated a retrospective study of prenatally diagnosed chromosomal abnormalities. From among a series of 3,862 genetic amniocenteses, 32 cases of fetal autosomal trisomy were diagnosed for which corresponding maternal serum and amniotic fluid alpha-fetoprotein data could be retrieved. From a second laboratory, nine additional cases were added. The maternal serum alpha-fetoprotein levels expressed as multiples of the median were significantly lower in distribution for these 41 women than those from a group of normal matched control subjects (p less than 0.001). Since maternal age is shown to be a less than adequate predictor of autosomal trisomic birth, we proposed that a low level of maternal serum alpha-fetoprotein obtained through routine screening may prove to be valuable in improving the prenatal detection of these serious anomalies.