Trial data demonstrate that mepolizumab, a humanized anti-interleukin 5 monoclonal antibody, is effective for patients with severe asthma and comorbid chronic rhinosinusitis (CRS) with nasal polyps. This real-world, retrospective cohort study investigated mepolizumab for US patients with severe asthma and CRS with/without sinus surgery. IQVIA PharMetrics Plus claims data from baseline and follow-up (12 months before and after mepolizumab initiation) were used to analyze three patient cohorts: cohort 1 (severe asthma only); cohort 2 (severe asthma+comorbid CRS without sinus surgery); and cohort 3 (severe asthma+comorbid CRS+sinus surgery), allowing for cross-cohort comparisons. The analysis included 495, 370, and 85 patients in cohort 1, cohort 2, and cohort 3, respectively. Systemic and oral corticosteroid use was lower for all cohorts after mepolizumab initiation. In cohort 3, asthma rescue inhaler and antibiotic use were lower during follow-up than baseline. Asthma exacerbations were reduced by 28% to 44% comparing follow-up versus baseline, with the largest reduction in cohort 3 (ratio of incidence rate ratio [RR] vs cohort 1: 0.76; p=0.036). Reductions in oral corticosteroid claims were greater following mepolizumab initiation for cohort 3 versus cohort 1 (RR, 0.72; p=0.011) and cohort 2 (RR, 0.70; p<0.01). In cohorts 1 through 3, outpatient and emergency department visits were reduced by 1 to 2 and 0.4 to 0.6 visits annually, asthma-related and asthma exacerbation-related total costs were reduced by $387 to $2580 USD, and medical costs were reduced by $383 to $2438 USD during follow-up. Consistent with trial data, mepolizumab use in real-world practice shows benefits across comorbid patient cohorts with more a pronounced impact in those with severe asthma+comorbid CRS+sinus surgery.