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Background: A short‐course oral corticosteroid taper and topical intranasal corticosteroids may be used to maximize the success of medical management for chronic rhinosinusitis with nasal polyps (CRSwNP). In this study, we sought to identify characteristics that would be predictive of efficacy for this combination regimen. Methods: Sixty‐four patients with CRS, bilateral polyps, a polyp score of at least 3, and a 22‐item Sino‐Nasal Outcome Test (SNOT‐22) score ≥20 were prospectively enrolled and uniformly treated with a 15‐day prednisone taper and twice daily dilute budesonide irrigations. Participants were assessed at enrollment and at follow up, 2 to 5 months later. Clinical and demographic characteristics were assessed at enrollment. At both time points, CRS symptoms were assessed with SNOT‐22, and polyp score (range, 0 to 6) was assessed endoscopically. Associations were determined with regression. Results: Pretreatment SNOT‐22 score (adjusted β = −0.83; 95% CI, −1.08 to −0.58; p < 0.001) and comorbid asthma (adjusted β = 15.75; 95% CI, 4.74 to 26.75; p = 0.007) were associated with a change in SNOT‐22 experienced over the study period. Achieving a greater‐than‐1 minimal clinically important difference (MCID) improvement in SNOT‐22 score was also associated with pretreatment SNOT‐22 score (adjusted OR = 1.09; 95% CI, 1.04 to 1.14; p < 0.001) and comorbid asthma (adjusted OR = 0.13; 95% CI, 0.03 to 0.72; p = 0.019). SNOT‐22 score ≥47 had 81.5% sensitivity and 78.4% specificity to detect patients experiencing 1 MCID improvement. Pretreatment polyp score was not associated with any outcome metric. Conclusion: In treatment of CRSwNP with prednisone and budesonide irrigations, pretreatment endoscopy was not informative of treatment response. Pretreatment SNOT‐22 and comorbid asthma may be more predictive. [ABSTRACT FROM AUTHOR]