Lower extremity varicose veins are a common condition in vascular surgery and proliferation of vascular smooth muscle cells (VSMCs) in the intima is a significant pathological feature of varicosity. However, the pathogenesis of varicose veins is not fully understood. Osteopontin (OPN) could promote the migration and adhesion of VSMCs through the cell surface receptor integrin beta 3 and the cooperation of OPN and integrin beta 3 is involved in many vascular diseases. However, the role of OPN and integrin beta 3 in varicosity remains unclear. In the current study, we found that the methylation levels in the promoter regions of OPN and integrin beta 3 genes in the VSMCs of varicose veins are reduced and the protein expression of OPN and integrin beta 3 are increased, compared with normal veins. Furthermore, it was observed that VSMCs in the neointima of varicose veins were transformed into the synthetic phenotype. Collectively, hypomethylation of the promoter regions for OPN and integrin beta 3 genes may increase the expression of these genes in varicosity, which is closely related to VSMC phenotype switching. Hypomethylation of the promoter regions for OPN and integrin beta 3 genes may be a key factor in the pathogenesis of varicosity.