We identified eight plasma proteins that are significantly associated with the risk of varicose veins after Bonferroni correction (P < 2.495 × 10−5), with five being protective (LUM, POSTN, RPN1, RSPO3, and VAT1) and three harmful (COLEC11, IRF3, and SARS2). This evidence concerns the gene IRF3 and Varicose veins.