A molecular mechanism responsible for varicose vein occurrence was investigated. The role of potential cell cycle regulator p21 and programmed cell death in the pathology leading to the proximal long saphenous vein (LSV) incompetence was investigated. Proximal LSV specimens were obtained from 40 patients with primary varicose veins who had undergone crossectomy. The expression of the p21, p53, and fas encoding genes was investigated by the means of real-time RT-QPCR. Immunostaining for gene product presence, proliferating cell nuclear antigen (PCNA), and apoptotic cells (TUNEL assay) was carried out. The results were compared to the control healthy vein specimens and correlated with pathologic examination findings (of the valve and vein structure). A significant increase in p21, p53, and fas mRNA expression were reported in the proximal incompetent veins. The expression of p21 correlated with expression of p53 (r = 0.658; p<0.05) and negative correlation between media apoptotic index and p21 mRNA expression was found (r = -0.493; p<0.05). Decrease in the muscular component within the media and disturbances of the local structure in the incompetent LSVs were reported. Fas overexpression did not correlate with p53 expression level and did not correlate with apoptotic cell number in the respective vein layers. PCNA-positive cells were present more frequently in the media of the control veins, especially in young subjects. Apoptosis downregulation, cell cycle inhibition and smooth muscle cell hypertrophy are important factors influencing vein wall disturbances related to sapheno-femoral junction incompetence.