INTRODUCTION: Current understanding of the immune landscape underlying allergic conjunctivitis (AC) remains rather limited. We investigated the potential association between circulating immunophenotypes and AC using Mendelian randomization (MR) methodology. METHODS: Based on genome-wide association studies (GWAS) summary-level statistics, a 2-sample MR was employed to analyze the bidirectional causal relationships between 731 circulating immunophenotypes and AC risk. RESULTS: A total of 33 genetically predicted immunophenotypes were significantly associated with AC risk. A protective effect of 18 immunophenotypes against AC was found, such as CD3 on CD39+CD8br (Inverse variance weighted [IVW] odds ratio [OR] = 0.936, 95% confidence interval [CI]: 0.925-0.985, p = 0.003) and CD25 on CD28+CD4+ (IVW OR = 0.921, 95% CI: 0.863-0.983, p = 0.013). Conversely, 15 immunophenotypes were found to be significantly associated with AC risk, such as CD25 on IgD-CD38dim (IVW OR = 1.042, 95% CI: 1.012-1.073, p = 0.006). Reverse MR based on these 33 genetically predicted immunophenotypes suggested that AC also had a significant influence on four circulating immune cells, including CD33-HLA DR- AC (IVW OR = 1.187, 95% CI: 1.034-1.362, p = 0.015), CD3 on CD39+CD8br (IVW OR = 0.876, 95% CI: 0.779-0.985, p = 0.027), HLA DR on CD14+ monocyte (IVW OR = 0.831, 95% CI: 0.725-0.953, p = 0.008), and CD39 on CD39+ secreting Treg (IVW OR = 1.123, 95% CI: 1.002-1.259, p = 0.046). CONCLUSION: Our study highlights the intricate association between immune cells and AC, providing a valuable basis for future mechanistic and therapeutic studies from an immunological perspective.