BACKGROUND: Varicose veins (VVs) are a common chronic venous disorder with a complex pathophysiology involving immune dysregulation, inflammation, and genetic predisposition. This study aims to identify immune-related causal factors in the pathogenesis of VVs using Mendelian randomization (MR). METHODS: A 2-sample MR analysis was conducted to assess the causal relationships between immune cell phenotypes and VVs. Genetic variants were used as instrumental variables, and data were derived from the Finland and genome-wide association study catalog. Inverse variance weighting (IVW) was used as the primary method, supported by sensitivity analyses such as MR-Egger, weighted median, and weighted mode. RESULTS: A total of 79 immunophenotypes were identified as significantly associated with VVs, including 19 related to B-cells, 6 to conventional dendritic cells, 6 to T-cell maturation stages, 6 to monocytes, 12 to myeloid cells, 11 to T cells, B cells, and natural killer cells, and 17 to regulatory T-cells (Tregs). Of these, 8 immunophenotypes remained significant after multiple testing correction (false discovery rate <
0.05). Specifically, high expression of cluster of differentiation 86 (CD86) on myeloid dendritic cells, CD33 expression on myeloid cells (e.g., basophils and human leukocyte antigen DR + subsets), increased side scatter area (SSC-A) on lymphocytes, and associations with CD39+ Tregs showed significant correlations with VVs. CONCLUSIONS: This study highlights the involvement of immune cells in the pathogenesis of VVs. High expression of CD86 on myeloid DCs and SSC-A on lymphocytes may serve as potential markers for predicting VVs risk, while the protective role of CD39+ Tregs suggests a new direction for immune modulation therapy. Further research is needed to validate these findings across diverse populations and explore their clinical applications.