Objective: To investigate the effects and the underlying mechanism of major vault protein (MVP) on the proliferation of arterial endothelial cells. Methods: Human aortic endothelial cell (HAEC) were infected with lentivirus to inhibit or overexpress MVP. Cell proliferation and death were detected with CCK-8 assay and flow cytometry. Apoptosis inhibitor Z-VAD and necroptosis inhibitor Nec-1 were used to distinguish the mode of cell death. Annexin V binding and Caspase 3 activity were detected by flow cytometry, and cleaved Caspase was examined by Western Blot. Real time PCR and Western Blot were performed to investigate target molecules and the regulatory relationship between target molecules and MVP. Results: Knockdown of MVP inhibited the proliferation activity of HAEC and promoted the HAEC cell death. Overexpression of MVP resulted in the opposite results. Treatment with Z-VAD reversed HAEC death caused by MVP knockdown, while Nec-1 did not. Consistently, TNF-α-induced HAEC apoptosis was inhibited by MVP overexpression and exaggerated by MVP knocked down. MVP promoted the transcriptional expression of cellular inhibitor of apoptosis proteins1 (cIAP1) by up-regulating interferon regulatory factor 2 (IRF2) protein expression. IRF2 knockdown reversed the increase in cIAP1 expression and decrease in apoptosis caused by MVP overexpression. Conclusion: MVP promoted cIAP1 transcription by up-regulating IRF2 protein expression, thereby inhibiting TNF-α-induced apoptosis and promoting the proliferation of arterial EC.