We conducted this sutdy to investigate whether patients with unexplained midtrimester elevation of maternal serum alpha-fetoproten (MSAFP) are at increased risk for adverse perinatal outcomes. The inclusion criteria for patients with unexplained MSAFP elevations were a MSAFP level 2.5 or greater multiples of median (MoM), a single gestation, a confirmed gestional age, and no fetal malformation or death on ultrasonography. Patients with MSAFP levels 0.25 to < 2.5 MoM served as controls Maternal blood as drawn at 15-20 weeks estimated gestional age. Of the 1,731 patients screened, 35(2.0%) had an unexplained elevated MSAFP level. 21 of 29 patients with unexplained MSAFP elevations accepted genetic amniocentesis and the fetal karyotypes were normal in all cases. Patients with unexplained MSAFP levels had significantly higher incidence of fetal congenital malformation (6.9% versus 1.0% ; P<.05) and fetal death (13.8% versus 0.4% ; P<.001) than those with normal MSAFP. But no significant differences were observed in the incidence of preterm delivery, intrauterine growth retardation, low birth weight, and pregnancy-induced hypertension. This study suggests that patients with unexplained midtrimester elevations of MSAFP are incresed risk for fetal congenital malformation and fetal death. Careful clinical follow-up elevations is warranted in these patients.