Objectives: Histamine has traditionally been recognized as a mediator that must be blocked in allergic responses. However, in the IgG-histamine complex (Histobulin), it paradoxically induces immune tolerance. While intravenous immunoglobulin (IVIG) exerts immunomodulatory functions through Fcγ receptor blockade and induction of regulatory pathways, the IgG-histamine complex uniquely provides histamine-driven tolerogenic effects. This study aimed to investigate both the clinical efficacy and mechanistic evidence underlying this paradoxical role of histamine. Methods: Clinical outcomes were evaluated in patients with chronic spontaneous urticaria, psoriasis, atopic dermatitis, and primary eosinophilic colitis who received Histobulin therapy. In parallel, in vitro and in vivo experiments were conducted to examine the effects of histamine pretreatment on mast cells. FcεRI-mediated degranulation, inflammatory cytokine release, and passive cutaneous/systemic anaphylaxis responses were analyzed. Results: Histobulin induced rapid clinical improvement and sustained remission in multiple patients, with some maintaining disease-free status for over one year. Mechanistically, histamine pretreatment suppressed FcεRI-mediated phosphorylation cascades in mast cells, activated SHP-1–mediated dephosphorylation, and significantly reduced degranulation and systemic anaphylaxis. These findings indicate that repeated histamine exposure induces immune tolerance rather than hypersensitivity. Conclusion: The IgG-histamine complex shows significant clinical efficacy across allergic and autoimmune conditions, supported by mechanistic evidence of histamine-induced mast cell tolerance. Future studies will clarify whether its tolerogenic effects converge with or diverge from IVIG-mediated immunomodulation, particularly in Fcγ receptor–bearing innate immune subsets.