BACKGROUND: Non-alcoholic fatty liver disease (NAFLD) is a globally widespread disease. Recent investigations have highlighted a close association between immunity and NAFLD, but the causality between them has not been thoroughly examined. METHODS: A total of 731 immunological traits and NAFLD cohorts were derived from genome-wide association study summary data, and single nucleotide polymorphisms significantly associated with immune traits were identified as instrumental variables. Moreover, 731 phenotypes include absolute cell counts, median fluorescence intensity (MFI), morphological parameters, and relative cell counts. The bidirectional two-sample Mendelian randomization (MR) was performed primarily using the inverse-variance weighted methods, and sensitivity analysis was carried out simultaneously. RESULTS: Four immunophenotypes were identified to exert a protective effect against NAFLD, including HLA-DR CONCLUSION: The study demonstrated a potential causal link between several immunophenotypes and NAFLD, which contributes to advancing research and treatment of NAFLD based on immune-mediated mechanisms.