<p>Susceptibility to SARS-CoV-2 infection and severity of COVID-19 have high heterogeneity, but the underlying factors for such heterogeneity were largely unknown. This study aimed to investigate whether genetically determined immune phenotypes contribute to the variability in COVID-19 outcomes, by integrating large-scale GWAS data to assess genetic correlations, causal associations, and pleiotropic gene functions. Based on the summary statistics from GWAS analyses for immune phenotypes and COVID-19 outcomes, comprehensive analyses were performed to elucidate the associations between immune phenotypes and COVID-19 pairs. The genetic correlations between COVID-19 outcomes and immune phenotypes were commonly observed, and 60 immune phenotypes were significantly correlated with four COVID-19 outcomes (64 pairs) (FDR &lt; 0.05). Treg T cell panel and B cell panel have relatively more significant pairs in number. Pairwise gene-based analyses identified numerous pleiotropic genes for significant pairs identified. The gene set enrichment analysis revealed the involvement of the identified pleiotropic genes in complex immune processes. We observed significant causal effects of six immune phenotypes from 4 trait panels on any one of the two COVID-19 outcomes, and of which CD19 on naïve-mature B cell was the only significant immune phenotype shared by the two COVID-19 outcomes. The findings greatly improved our understanding of the interaction between immune response and COVID-19 outcome, and also contribute to the detection of susceptible individuals and the design of therapeutic strategies from the perspectives of immunology. In conclusion, our study provides genetic evidence that immune phenotypes, particularly B cell and Treg traits, play a causal role in susceptibility to SARS-CoV-2 infection and progression to severe COVID-19.</p>