Expectant mothers who smoke have higher levels of maternal serum alpha-fetoprotein and lower levels of unconjugated estriol and total human chorionic gonadotrophin than non-smoking mothers. This significantly affects performance of screening for Down's syndrome. This study includes 22,169 pregnant women: 18,876 non-smokers, 2,660 smoking < or = 10 cigarettes/day, and 633 smoking > 10 cigarettes/day. Mean maternal age (32.6 years), maternal weight (60.5 kg), and gestational age (114.7 days) were similar or only slightly different between the three groups. To verify the effects of smoking on screening, we studied retrospectively 130 sequential Down's syndrome cases (47 from the screening program, 83 from the prenatal diagnosis program). The proportion of smokers in the Down's syndrome and unaffected pregnancies was similar, whilst the false-positive rate and detection rate, based on fetal outcome, differed: false-positive rates were 5.63% in smokers and 9.42% in non-smokers, and detection rate 55.6% in smokers and 83.0% in non-smokers. Since the prevalence of Down's syndrome pregnancies was the same at mid-trimester in smokers and non-smokers and the proportion of smokers was not related to maternal age, we propose an adjustment of the Down's syndrome risk evaluation algorithm according to smoking habits.