OBJECTIVES: A large number of studies suggest that abnormalities in nitric oxide (NO) synthesis may contribute to the development of preeclampsia. We recently identified a variant within exon 7 of the endothelial NO synthase (eNOS) gene: G to T conversion at nucleotide position 894 resulting in replacement of glutamic acid with aspartic acid at codon 298 (Glu298Asp). We analyzed the association between the Glu298Asp eNOS gene variant and preeclampsia. STUDY DESIGN: The study included 152 preeclampsia patients (35 mild, 80 severe, and 37 superimposed) and 170 control subjects. Screening for the Glu298Asp eNOS gene variant was carried out by analysis of polymerase chain reaction-restriction fragment length polymorphism. RESULTS: The frequency of the Glu298Asp variant was significantly higher in the severe preeclampsia group (28.8%) than in the control (14.1%; p < .01), superimposed preeclampsia (8.1%, p < .01), and mild preeclampsia (11.4% p < .01) groups. CONCLUSIONS: We conclude that the presence of the Glu298Asp eNOS gene could be a marker of increased risk of developing severe preeclampsia. (J Soc Gynecol Investig 2000;7:238-41) Copyright (C) 2000 by the Society for Gynecologic Investigation.