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This review examines the immunologic and clinical considerations surrounding biologic therapy for chronic rhinosinusitis with nasal polyps (CRSwNP), focusing on adverse events, hypersensitivity reactions, excipient-related reactions, and practical allergological evaluation. Importantly, the majority of adverse events reported with biologic therapies represent non-immune-mediated side effects rather than true hypersensitivity reactions. A structured diagnostic approach is essential to distinguish IgE-mediated, non-IgE-mediated, immune complex, excipient-driven, and paradoxical immune-mediated reactions to ensure safe continuation or appropriate switching of therapy. Consequently, we integrate excipient-related reactions within the broader framework of immunologic and non-immunologic adverse events. Recent published real-world studies and pharmacovigilance analyses show that dupilumab, mepolizumab, omalizumab, tezepelumab and depemokimab are highly effective but associated with distinct adverse profiles, including ocular inflammation, arthralgia, serum-sickness–like reactions, and rare anaphylaxis. Increasing attention has been given to polysorbates and polyethylene glycol (PEG), synthetic surfactants/stabilizers that can trigger immediate hypersensitivity in sensitized individuals. Updated EAACI/ENDA recommendations support structured testing, provocation, and selective desensitization. Biologic therapy has transformed CRSwNP management. Most adverse reactions are non‑allergic; however, systematic allergological evaluation is essential to differentiate drug‑specific immune reactions from excipient hypersensitivity and paradoxical immune syndromes. Improved ingredient transparency, standardized testing, and vigilant pharmacovigilance will optimize long-term safety and guide future research.