Objectives: The aim of this review is to draw attention to key findings from various published studies concerning the effect of methylcobalamin/cyanocobalamin on the immune response of patients diagnosed with pernicious anemia (PA).

Methods: This systematic review followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines to ensure the accuracy and reliability of the included randomized controlled trials (RCTs) evaluating the impact of vitamin B12, in either natural or synthetic form, on immune function in patients with PA. The protocol was registered with PROSPERO (CRD42024518621).

Results: Methylcobalamin/Cyanocobalamin administration in PA patients significantly increased CD3, CD8+, and CD19 cell levels, restoring them toward normal. Natural Killer (NK) cell activity improved, while the CD4/CD8 ratio decreased. These findings indicate a potential enhancement of immune function in PA patients.

Conclusion: Significant restoration of CD3, CD8+, and CD19 cell counts was observed in PA patients after vitamin B12 administration, whether in its natural (methylcobalamin) or synthetic (cyanocobalamin) form. Additionally, NK cell activity was improved, and the CD4/CD8 ratio decreased. These findings suggest that methylcobalamin/cyanocobalamin has the potential to significantly enhance immunity in patients with PA. Therefore, we recommend conducting well-designed, large-scale Phase II and Phase III clinical trials with standardized methodologies to validate these findings and provide more robust evidence on the immunomodulatory effect of vitamin B12 in PA patients.