Background: Chronic rhinosinusitis (CRS) has a prevalence of up to 11% in Europe and the USA, making it one of the most common chronic diseases. Classification based on immunological endotypes is increasingly being integrated into the disease definition, particularly for chronic rhinosinusitis with nasal polyps (CRSwNP). Depending on the specific mechanisms underlying chronic tissue inflammation, different endotypes are characterized. Genetic and epigenetic changes in the mucosal immune system play a significant role in this context. Identifying endotypes can help to better understand disease heterogeneity and develop personalized treatment approaches. In part 1 of this publication, we discussed the immunological classifications of type IV hypersensitivity reactions (T1-, T2-, and T3-endotypes), while part 2 focused on type V hypersensitivity reactions (epithelial barrier defects). The aim of part 3 is to describe type VI hypersensitivity immune reactions and highlight their implications for extended diagnostics and treatment. Methods: The European Academy of Allergy and Clinical Immunology (EAACI) recently published a position paper presenting an updated nomenclature for immunological hypersensitivity reactions, now encompassing nine distinct immunological reaction types. The antibody-mediated reactions originally classified by Coombs and Gell as types I, II, and III have been expanded and described in greater detail. Direct cellular and inflammatory responses to chemical substances are defined as type VI hypersensitivity reactions and are the focus of this third part of the publication series. Results: In CRSwNP patients with type VI hypersensitivity immune reactions, an imbalance between cyclooxygenase (COX) isoforms 1 and 2 can be observed. This imbalance is exacerbated by COX-1-inhibiting drugs, leading to reduced prostaglandin E2 (PGE2) synthesis and overproduction of leukotriene C4 (LTC4) and PGD2. As a result of the chronic mucosal inflammation, alarmins such as interleukin-33 (IL-33) and thymic stromal lymphopoietin (TSLP) are released. These cytokines activate Th2 lymphocytes and type 2 innate lymphoid cells (ILC2s), prompting the release of cytokines such as IL‑4, IL‑5, and IL-13. Conclusion: Expansion of the immunological classification to include type VI hypersensitivity reactions represents an important step toward a better understanding of the pathophysiology of CRSwNP. Identifying these specific reaction patterns—particularly those triggered by chemical substances—highlights the complexity of the underlying immune mechanisms and emphasizes the need for endotype-based diagnostics. Incorporating these insights into clinical practice allows for more targeted individualized therapies and marks another step toward personalized medicine in CRS.