We sought to determine whether nuchal translucency (NT) thickness of >or= 2 mm poses a risk for adverse perinatal outcome. A prospective observational study was conducted including all singleton pregnancies undergoing NT screening between 11 and 13.6 weeks' gestation, from January 1999 to October 2006, in a University Medical Center. Aneuploid and malformed fetuses were excluded from the analysis, as well as fetuses from pregnancies that ended before 22 gestational weeks. A comparison was performed between fetuses with NT of >or= 2 mm and those with NT < 2 mm. Stratified analyses using the Mantel-Haenszel technique and multivariable analyses were performed to control for confounders. A total of 2205 singleton fetuses with normal karyotype were evaluated during the study period. Of these, 2.0% ( N = 45) had NT of 2 mm and above. Pregnancies with NT of >or= 2 mm were significantly associated with diabetes mellitus (either gestational or pregestational; odds ratio [OR] = 2.3, 95% confidence interval [CI] 1.02 to 5.1; P = 0.023). Higher rates of perinatal mortality (OR = 17.5, 95% CI 4.5 to 61.8; P < 0.001) and stillbirth in particular (OR = 25.6, 95% CI 4.9 to 120.7; P < 0.001) were noted among pregnancies with NT >or= 2 mm. Using a multivariable analysis and controlling for confounders such as diabetes mellitus and the crown-rump length, NT >or= 2 mm was found to be an independent risk factor for perinatal mortality (adjusted OR 14.3; 95% CI 1.8 to 3.5; P < 0.001). Nuchal translucency thickness of >or= 2 mm in euploid, anatomically normal fetuses poses a significant risk for adverse perinatal outcome.