Background. In many pre-eclamptic women the placentation process seems to be disturbed. Our objective was to investigate if disturbed placentation in pre-eclamptic women may be recognized in early second trimester as altered plasma levels of factors involved in the formation of the uteroplacental unit.Methods. In a prospective study of 2190 pregnant women we compared plasma leptin, transforming growth factor-β 1 (TGF-β 1 ) and plasminogen activator inhibitor type 2 (PAI-2) concentrations at 18 weeks' gestation in 71 women with subsequent pre-eclampsia and 71 controls matched for age, parity and first trimester body mass index.Results. Leptin and TGF-β 1 concentrations were lower and PAI-2 concentration higher in women destined to develop pre-eclampsia relative to controls (leptin: median (25-75 percentiles): 19.0 (14.5-29.0) vs 25.0 (16.0-35.0)ng/ml (p =0.03), TGF-β 1 : 3.2 (2.0-6.1) vs 5.3 (3.8-7.1)ng/ml (P=0.01) and PAI-2: 78.8 (65.1-118.1) vs 67.6 (61.6-79.6)ng/ml (P=0.002)). OR (95 per cent CI) for pre-eclampsia for women in the upper quartile compared to women in the lower quartile were: leptin: 0.2 (0.03-0.7), TGF-β 1 : 0.2 (0.08-0.7) and PAI-2: 3.1 (1.2-8.2).Conclusions. Altered plasma concentrations levels of factors involved in the process of placentation in women destined to develop pre-eclampsia, indicate that disturbed formation of the uteroplacental unit is reflected in the maternal circulation before 20 weeks' gestation.