Our study found that high PVT1 expression in HCC cells is associated with high unmethylation in PVT1 promoter region. IFN-a treatment further increases PVT1 expression in HCC cells by enhancing H3K4me3 modification on the promoter. Furthermore, PVT1 knockdown enhances IFN-a-induced HCC cell apoptosis by promoting phosphorylation of signal transducer and activator of transcription 1 (STAT1) and upregulating IFN-stimulated genes expression. Moreover, PVT1 specifically interacts with STAT1 in HCC cells. Taken together, these results for the first time indicate that IFN-a treatment promotes oncogenic PVT1 expression in HCC cells, which interacts with STAT1 to inhibit IFN-a signaling, ultimately blocking IFN-a-induced cells apoptosis, suggesting that lncRNA PVT1 may be a potential target to improve IFN-a-mediated HCC immunotherapies.