BACKGROUND: A functional single-nucleotide polymorphism of the gene for catechol-O-methyltransferase (COMT) results in a valine to methionine mutation at position 158 (Val158Met). The valine variant catabolizes the introduction of a methyl group to 2-hydroxyestradiol to form 2-methoxyestradiol (2ME) at a higher rate of its methionine counterpart. Preeclampsia (PE) is a major obstetric problem and a significant source of maternal and fetal morbidity and mortality (Sibai, 2005), complicating an estimated 2% of all pregnancies (Duley, 2003). Several studies have suggested that the main features of PE are consequences of endothelial dysfunction related to excess circulating anti-angiogenic factors, most notably, soluble sVEGFR-1 (sFlt-1) and as well as to decreased placental growth factor levels (PlGF)(Munaut, 2012). A key factor connecting the angiogenic imbalance with generalized endothelial dysfunction in PE has been suggested to be a reduction in the synthesis of 2ME (Kanasaki, 2008). AIM: We investigated the relationship between COMT Val158M polymorphism and the risk of preeclampsia. METHODS: A total of 54 preeclamptic women and 72 normotensive women were enrolled in a prospective study. We gathered information on maternal history with both maternal and placental COMT Val158Met polymorphism and blood biomarkers of pregnancy hypertensive disorders. COMT Val158Met polymorphism was genotyped by quantitative fluorescent-polymerase chain reaction. Serum levels of maternal PlGF and sFlt-1 and plasmatic levels of 2ME were measured by ELISA. Student’s t-test was used to compare 2ME means levels between case and control subjects. Multiple logistic regression analysis was used to estimate the adjusted risk of preeclampsia according to levels of 2ME and genotypes. Multiple lineal regression was used to explore the adjusted association between 2ME and both PlGF and PLGF levels respectively. Covariates taken into account in all the analyses: smoking habit, body mass index, maternal age and nulliparity. RESULTS: Controls had a significantly higher levels of plasmatic 2ME than preeclamptics (t=-4.45, p<0.001) (2697.03±188.34 vs1878.26±183.52 pg/m). The adjusted odds ratios (adjOR) was 0.05 [95%, Confidence interval (CI):0.01,0.25] with a p-value<0.001. The adjOR for maternal met/met vs not-met/met was 1.54 [95% CI: 0.57,4.17] with a p-value=0.390. Fetal met/met vs not-met/met was 3.27 [95%CI: 1.06,10.09] with a p-value=0.039. 2ME levels were significantly negatively associated with sFlt-1 [B=-0.26, [95% CI: -0.42,-0.11)]; p=0.001] and significantly positively associated with PlGF levels [B=0.31, (95% CI: 0.18,0.45); p<0.001].CONCLUSION: These findings suggest that homozygosity for fetal COMT met/met genotype and reduced 2ME levels may increase susceptibility to preeclampsia.