Abstract Body: The transition of smooth muscle cells (SMCs) from a contractile to a synthetic phenotype is a key contributor to cardiovascular disease (CVD) pathologies, such as atherosclerosis and in-stent restenosis. We previously reported that loss of leiomodin 1 (LMOD1), a coronary artery disease risk gene highly expressed in SMCs, promotes SMC phenotypic switching in vitro. However, the in vivo role of LMOD1 and the molecular mechanisms driving this transition remain unknown. In this study, we found that Lmod1 heterozygous mice subjected to carotid artery ligation developed larger neointimal lesions. Histopathological analyses attributed this phenotype to increased SMC proliferation. RNA sequencing studies of LMOD1-deficient SMCs revealed a significant upregulation of genes associated with increased cell proliferation, particularly those involved in the G1/S phase transition. Further analysis identified cyclin-dependent kinase 6 (CDK6) as a potential mediator of this hyperproliferative response. Notably, the knockdown of CDK6 in LMOD1-deficient cultured SMCs restored SMC proliferation to near baseline levels, indicating that the observed phenotype is reversible in vitro. Collectively, these findings indicate that LMOD1 deficiency promotes SMC proliferation by upregulating CDK6 expression and provide mechanistic insight into how reduced LMOD1 expression may contribute to increased neointimal lesion size and vascular remodeling.