Objective: To study the role of placenta fibrinogen-like 1 (FGL1) during pre-eclampsia (PE) progression. Design: A case-control study combined with the experimental research of the cellular and PE mouse model. Setting: FGL1 is a protein involved in liver regeneration, but its role in the placenta and PE remains uninvestigated. Population or Sample: Serum and placenta from the PE mouse model and in women with (n = 38) and without (n = 42) PE were analyzed. Methods: Pregnant C57Bl/6 mice (n = 6) were administered L-NAME subcutaneously with or without FGL1 once daily starting on day 7–14 of pregnancy until sacrifice. Maternal body weight, blood pressure, urinary protein, weight and length of the placenta and fetus were assessed. The placental structure was evaluated using histochemistry staining. The sera of pregnant women during the late trimester were quantified with ELISA. Main Outcome Measures: FGL1 expression in serum and placenta during PE, and treatment outcome of FGL1. Results: FGL1 expression in both serum and placenta was significantly upregulated in patients with PE and mice compared with control groups. FGL1 treatment decreased maternal hypertension, and proteinuria, ameliorated fetal weight in PE mice, downregulated proinflammatory cytokines (interleukin-1b and -6), and maintained the balance between antiangiogenic (sFlt-1, soluble fms-like tyrosine kinase-1) and proangiogenic substances (Pgf, placental growth factor) in the placenta. Conclusions: Placental FGL1 upregulation plays a pivotal role in reducing PE progression. Funding: Ministry of Science and Technology (MOST 106-2314-B-006-066, 108-2314-B-006-062), Taiwan; National Cheng Kung University Hospital (NCKUH-10604002, NCKUH-10705015, NCKUH-10902008); Kaohsiung Medical University (KMU-TC108A02, KMUH-DK(A)110003)