Background: To explore the value of serum soluble fms-like tyrosine kinase 1 (sFlt-1), CXC chemokine ligand 16 (CXCL16), and lipocalin 2 (LCN-2) in the diagnosis and grading of preeclampsia (PE).Methods: A total of 186 patients with PE diagnosed and treated in our hospital were included. According to the disease severity, the patients were divided into the mild PE group (99 cases) and the severe PE group (87 cases). A total of 72 healthy pregnant women who underwent antenatal care were selected as the healthy control group. The levels of serum sFlt-1, CXCL16, and LCN-2 before medication were compared among the patients, and the diagnosis and grading value of the above 3 indicators were analyzed. Results: For PE patients vs. healthy controls, the levels of sFlt-1 (132.71±14.49 vs. 68.43±9.28 μg/L), CXCL16 (2.15±0.35 vs. 0.61±0.12 μg/L), and LCN-2 (70.81±8.25 vs. 19.22±3.14 μg/L) were all significantly higher in PE patients than in the healthy controls (P<0.05). For severe PE vs. mild PE, the levels of sFlt-1 (142.16±20.23 vs. 124.41±10.36 μg/L), CXCL16 (2.87±0.59 vs. 1.51±0.28 μg/L), and LCN-2 (90.76±10.16vs. 53.27±6.19 μg/L) in the severe PE group were higher than those in the mild PE group (P<0.05). Receiver operating characteristic curve (ROC) analysis showed that when the cut-off values of sFlt-1, CXCL16, and LCN-2 were 99.65, 1.36, and 0.84 μg/L, respectively, the diagnostic efficacy of PE was the highest. With these cut-off values, the diagnostic sensitivities of sFlt-1, CXCL16, and LCN-2 were 86.67%, 73.33%, and 93.33%, respectively. The specificities of sFlt-1, CXCL16, and LCN-2 were 80.00%, 86.67%, and 60.00%, respectively. The areas under the curves (AUC) of sFlt-1, CXCL16, and LCN-2 were 0.764, 0.769, and 0.831, respectively. When the cut-off values for sFlt-1, CXCL16, and LCN-2 were 135.16, 2.24, and 70.38 μg/L, respectively, the efficacy was the highest in distinguishing mild and severe PE. With these cut-off values, the AUC values of sFlt-1, CXCL16, and LCN-2 were 0.837, 0.808, and 0.869, respectively.Conclusions: sFlt-1, CXCL16, and LCN-2 have certain significance in the diagnosis and grading of PE.Among them, LCN-2 has the highest correlation with the diagnosis and grading of PE.