: Metastasis is the leading cause of the high morality of esophageal squamous cell carcinoma (ESCC), so early monitoring metastasis of esophageal cancer is the key to improve the survival rate of ESCC patients. However, there have not been effective biomarkers for predicting metastasis of ESCC patients,it is an urgent need to identify ESCC metastasis-related proteins. : iTRAQ-based proteomic method was performed in highly metastatic 30M cell established in our previous study and the corresponding parental cells KYSE30.The expression of IFI16 was verified using western blotting and immunohistochemistry (IHC). Then, cck8, transwell assay,mouse metastasis experiments were performed to determine the functional role of IFI16 in esophageal cancer. Finally, RAN-Seq, qpcr, transwell assay were used to investigate the underlying mechanism of IFI16 in esophageal cancer metastasis. : The data showed that IFI16 was upregulated in 30M cell compared with KYSE30 cell. IFI16 also increased in ESCC tumor compared with non-tumor tissue. Kaplan-Meier survival curve analysis showed that the relapse-free survival (RFS) of patients with high IFI16 level was worse than that of patients with low IFI16 level (P=0.0449). In addition, IFI16 knockdown did not affect the cell growth, but inhibited ESCC cell migration and invasion in ESCC cells. Moreover, IFI16 knockdown suppressed the lung metastasis of 30M cells in mouse models. Finally, we performed an RNA-Seq assay in IFI16-knocking down 30M cells and identified that knocking down IFI16 downregulated the expression of fibroblast growth factor proteins (FGF1, FGF2 etc.). Furthermore, overexpressing FGF1 and FGF2 rescued the lost of migration and invasion ability of 30M mediated by IFI16 knockdown. : Our results demonstrated that IFI16 was a key ESCC metastasis-related protein and played a role in ESCC metastasis through promoting the FGF proteins expression.