Preeclampsia is a pregnancy-related disorder characterized by hypertension and proteinuria, affecting about 5-8% of pregnancies. It is a major cause of fetal and maternal morbidity/mortality. The disease is most probably multifactorial and caused by several placental dysfunctions. As an important mediator, sFLT1 is induced in the placenta and in the serum of preeclamptic women, acting as a decoy receptor for placenta like growth factors (PLGF) and inducing an antiangiogenic balance. RNAi mediated gene specific silencing could represent a new therapeutic option in preeclampsia management. We tested sFLT1-specific small interfering RNA (siRNA) formulated with the liposomal siRNA delivery system AtuPLEX for the ability to ameliorate symptoms without deteriorating fetal health in an established rat model of preeclampsia. Transgenic rats expressing human angiotensinogen (hAGT) and renin (hREN) were crossed to produce a model of preeclampsia (PE rat) in the dams. Beginning on day 7 of gestation, transgenic hAGT dams were dosed intravenously with 2.8 mg/kg siRNA every third day through gestational day 19. Mean blood pressure was continuously recorded by radiotelemetry and 24 hour urine samples were collected in metabolic cages at day 17/18 of gestation. Rats were euthanized at day 21 of gestation. Biodistribution experiments showed that sFLT1 siRNA formulated with AtuPLEX delivers siRNA to the placenta but not to the embryo. In PE rats, our treatment was able to decrease sFLT1 mRNA expression in placenta, especially in the labyrinth layer. Circulating sFLT1 was also reduced by FLT1 siRNA treatment but did not show statistical significance. Silencing of sFLT1 did not prevent blood pressure increase in the last third of pregnancy in our preeclamptic rat model (159 ± 5 mmHg vehicle vs. 152 ± 2 mmHg sFLT1 siRNA). Proteinuria was not ameliorated (5712 ± 2038 μg/d vehicle vs. 3585 ± 1301 μg/d sFLT1 siRNA). In addition, sFLT1 siRNA had no influence on IUGR, measured by brain to liver weight ratio. AtuPLEX formulated siRNA specifically silenced maternal and placental sFLT1. The mode of delivery appears to be safe for fetal health. However, this sFLT1 knock down showed no protective effect on the preeclamptic phenotype in this Ang-II-based model.