Objective To explore the effect of transcription factor E-twenty-six variant gene 5 (ETV5) on the phenotypic switching of vascular smooth muscle cells (VSMCs). Methods The VSMCs were transfected with adenovirus vector overexpressing ETV5 in Ad-ETV5 group and green fluorescent protein (GFP) in Ad-GFP group. The VSMCs were transfected with human ETV5-specific small interfering RNA (siRNA) in platelet-derived growth factor (PDGF)-BB+siRNA_ETV5 group and siRNA with random negative sequence in PDGF-BB+siRNA_scramble group before inducing with PDGF-BB. The qPCR and Western blotting analysis were used to detect mRNA and protein levels of phenotypic switching markers of VSMC, including α-smooth muscle actin (α-SMA) and myosin heavy chain 11 (MYH11). Scratch wound assay and CCK-8 assay were performed to identify the proliferation and migration of VSMCs. Results Compared with the Ad-GFP group, the expressions of mRNA and protein of α-SMA and MYH11 were significantly decreased in the Ad-ETV5 group (P<0.05), while the abilities of proliferation and migration were significantly improved (P<0.05). Compared with PDGF-BB+siRNA_scramble group, the expressions of mRNA and protein of α-SMA and MYH11 were significantly increased in the PDGF-BB+siRNA_ETV5 group (P<0.05), while the abilities of proliferation and migration were significantly inhibited (P<0.05). Conclusion ETV5 may play an important role in the phenotypic switching of VSMCs.