The purpose of this study was to determine if an elevated concentration of soluble fms-like tyrosine kinase-1(sFlt-1) in maternal plasma and amniotic fluid is a risk factor for the subsequent development of preeclampsia. A case-control study was conducted to compare mid-trimester concentrations of maternal plasma and amniotic fluid sFlt-1 in patients who developed preeclampsia with those who did not. The study included 32 cases with preeclampsia (18 cases: severe preeclampsia) and 128 matched controls with normal outcomes. Patients with an abnormal fetal karyotype or major anomaly, multiple pregnancies, chronic hypertension, diabetes, and renal disease were excluded. Soluble Flt-1 concentration was measured by specific immunoassay. Nonparametric techniques were used for statistical analysis. 1) The median maternal plasma, but not amniotic fluid, sFlt-1 concentration in patients who developed preeclampsia was significantly higher than in the control cases (maternal plasma: median 730 pg/mL, range 60-3375 pg/mL vs median 441 pg/mL, range 58-1959 pg/mL, P < .05; amniotic fluid: median 10,504 pg/mL, range 5253-38,023 pg/mL vs median 10,236 pg/mL, range 4326-87,684 pg/mL, P = .65). 2) The median plasma concentration of sFlt-1 was higher in cases of severe preeclampsia than in those with mild preeclampsia without reaching statistical significance (median 762 pg/mL, range 261-3309 pg/mL vs median 334 pg/mL, range 60-3375 pg/mL; P = .07). However, there was no significant difference in the median amniotic fluid sFlt-1 concentrations between patients with severe preeclampsia and those with mild preeclampsia (P = .45). 3) An elevated maternal plasma sFlt-1 concentration (higher than 700 pg/mL) is a risk factor for the development of preeclampsia (OR 3.9, 95% CI 1.7-8.6) and severe preeclampsia (OR 7.4, 95% CI 2.5-22.1) after genetic amniocentesis. 4) The median interval from amniocentesis to the diagnosis of preeclampsia in patients with maternal plasma sFlt-1 concentrations higher than 700 pg/mL was 117 days (range 19-154 days). An elevated concentration of sFlt-1 in maternal plasma at the time of mid-trimester amniocentesis is a risk factor for the subsequent development of preeclampsia.