Objectives: Our aim was to evaluate the effect of fetal sex, smoking and body mass index (BMI) on nuchal translucency (NT). Methods: We analyzed data from 7,357 women with a normal singleton live birth outcome with information on smoking, BMI and sex of the infant. NT measurements were converted to multiples of the median (MoM(NT)) using a previously reported linear regression analysis. Results: The odds ratio (OR) for MoM(NT) >95th centile was 1.5 (95% CI 1.2-1.9) for smokers compared to nonsmokers and 1.4 (95% CI 1.1-1.7) for male fetuses compared to female fetuses. Obese women (BMI >/=30) had an increased OR for a large NT of 1.7 (95% CI 1.2-2.6) compared to normal weight women. Obese smokers carrying a male fetus had an OR of 4.2 (95% CI 1.7-10.1) of a MoM(NT) >95th centile compared to normal weight nonsmoking women with a female fetus. The effects of smoking, obesity status and fetal sex were independent of each other. Conclusions: Smoking, obesity and male sex are associated to a MoM(NT) >95th centile. This may affect screening performance and entail unnecessary anxiety in these women. Further investigations, including fetuses with adverse outcome, are needed.