Background and aims: Despite the advantage of arterial expansion for life-threatening vascular pathologies, the occurrence of neointima formation remains a prominent complication, with the underlying mechanisms largely unknown. A disintegrin and metalloprotease 22 (ADAM22) belongs to the family of ADAMs that possesses various biological capacities regulating vascular physiopathology. However, little is known about ADAM22 in vascular smooth muscle cell (VSMC)-mediated neointima formation. Here, we aimed to evaluate the potential functional regulation of ADAM22 in neointima formation and to further explore the underlying mechanisms. Methods: In our study, platelet-derived growth factor-BB (PDGF-BB)-induced VSMC proliferation was examined using a 5-bromo-2'-deoxyuridine (BrdU) incorporation assay and a cell counting kit-8 (CCK8) assay, while VSMC migration was detected using a modified Boyden chamber method and a scratch-wound assay. The functional role of ADAM22 in neointima formation was evaluated based on a left carotid artery wire injury model in mice at 14 and 28 days. Results: ADAM22 was significantly up-regulated in both PDGF-BB-challenged VSMCs and restenotic arteries of mice. When ADAM22 was overexpressed in VSMCs, cell proliferation, migration and phenotypic switching were simultaneously aggravated, whereas the opposite was observed when ADAM22 was knocked down in vitro. In ADAM22 heterozygote mice, wire-injury induced neointima formation was significantly ameliorated compared to wild-type control mice. Mechanistically, significantly up-regulated ERK phosphorylation is closely involved in the regulatory effects of ADAM22 in neointima formation. Interestingly, an ERK inhibitor largely reversed the aggravated VSMCs migration, proliferation and phenotypic switching induced by ADAM22 overexpression. Conclusions: Our results indicate that ADAM22 accelerates neointima formation by enhancing VSMC migration, proliferation and phenotypic switching via promoting ERK phosphorylation. Suppressing ADAM22 expression may be an effective strategy for ameliorating neointima formation.