ObjectiveTo compare the efficacy of th2‐targeted biologic medications (dupilumab, omalizumab, and mepolizumab) on absolute risk reduction (ARR) of functional endoscopic sinus surgery (FESS) in patients with chronic rhinosinusitis with nasal polyposis (CRSwNP) and allergic fungal rhinosinusitis (AFRS).MethodsThe TriNetX Research Network database was queried for each mAb's market lifespan through March 2024. Adults with CRSwNP were propensity score matched against non‐mAb controls based on age, sex, race, and asthma diagnosis. The primary outcome was rate of FESS, with secondary outcomes including inpatient admission, emergency department (ED) visit, and incidence of acute sinusitis. Subgroup analysis was performed for patients with AFRS.ResultsAll mAbs decreased FESS risk (dupilumab, ARR 11.48%, 95% CI 9.82%–13.15%, p < 0.001; omalizumab, ARR 12.02%, 95% CI 4.36%–19.68%, p = 0.002; mepolizumab, ARR 10.32%, 95% CI 5.24%–15.40%, p < 0.001) in CRSwNP patients. Only dupilumab also reduced risk of inpatient admission (ARR 8.59%, 95% CI 7.04%–10.15%, p < 0.001), ED visit (ARR 5.94%, 95% CI 4.28%–7.61%, p < 0.001), and acute sinusitis (ARR 2.60%, 95% CI 1.09%–4.12%, p = 0.001). In AFRS patients, only dupilumab reduced the risk of all outcomes: FESS (ARR 6.97%, 95 CI 2.86%–11.09%, p = 0.001), inpatient admission (ARR 16.93%, 95% CI 11.30%–22.57%, p < 0.001), ED visit (ARR 13.15%, 95% CI 7.15%–19.14%, p < 0.001), and acute sinusitis (ARR 7.17%, 95% CI 2.18%–12.17%, p = 0.005).ConclusionAlthough all mAbs reduced FESS risk in CRSwNP, only dupilumab reduced secondary outcomes as well. Similarly, only dupilumab improved all outcomes in AFRS patients. These data demonstrate the potential of mAbs in reducing disease burden and enhancing patient outcomes in CRSwNP and AFRS.Level of EvidenceNA Laryngoscope, 2024