Objectives/Hypothesis: Dupilumab, a fully human monoclonal antibody that blocks the shared interleukin (IL)-4/IL-13 receptor component, significantly improved outcomes for patients with chronic rhinosinusitis with nasal polyps (CRSwNP) in the SINUS-24 and SINUS-52 studies. This post hoc analysis evaluated dupilumab's effect on patient-reported symptoms and objective outcome measures using thresholds of clinically meaningful within-patient change from baseline. Methods: Patients with CRSwNP receiving subcutaneous dupilumab or placebo every 2 weeks in SINUS-24/SINUS-52 were analyzed. Patients recorded severity of nasal congestion (NC), loss of smell (LoS), and anterior/posterior rhinorrhea (each within range 0–3) daily. Total Symptom Score (TSS) was calculated as a composite severity score (0–9) for these symptoms. Objective measures included University of Pennsylvania Smell Identification Test (UPSIT; 0–40), nasal polyps score (NPS; 0–8), and Lund–Mackay computed tomography score (LMK-CT; 0–24). Thresholds of within-patient change in scores from baseline at weeks 24 and 52 considered clinically meaningful were ≥1.0 (NC, LoS), ≥3.0 (TSS), ≥8.0 (UPSIT), ≥1.0 (NPS), and ≥5.0 (LMK-CT). Results: A total of 724 and 303 patients were included in the week 24 and 52 analyses, respectively. Responder rates were significantly higher with dupilumab versus placebo at week 24 for NC (64% vs. 24%), LoS (63% vs. 14%), TSS (62% vs. 15%), UPSIT (54% vs. 6%), NPS (63% vs. 14%), and LMK-CT (59% vs. 3%); all P <.0001. Results were consistent at week 52. Conclusion: Significantly greater proportions of dupilumab-treated patients with CRSwNP compared with placebo demonstrated clinically meaningful improvements in patient-reported sinonasal symptoms and objective outcomes. Level of Evidence: 2 Laryngoscope, 132:259–264, 2022.