There are no head-to-head studies for patients with aspirin-exacerbated respiratory disease (AERD) comparing any of the 5 Food and Drug Administration-approved respiratory biologic therapies. Explore outcomes in subjects with AERD using biologic therapies in a real-world clinic setting. A retrospective pilot study was conducted for subjects with AERD who had been prescribed omalizumab (anti-IgE), mepolizumab (anti-IL-5), reslizumab (anti-IL-5), benralizumab (anti-IL-5 receptor alpha [anti-IL-5Rα]), or dupilumab (anti-IL-4 receptor alpha [anti-IL-4Rα]). Clinical outcomes pre- versus postinitiation of biologic therapy were explored including symptoms, 22-item sino-nasal outcome test scores, systemic corticosteroid and antibiotic prescriptions, and emergency room visits related to AERD. Of the 74 subjects, 58.1% (n= 43) had used 1 biologic, though many (41.9%, n= 31) trialed more than 1 biologic. Of the 50 subjects who had used anti-IL-4Rα therapy, 98% (49 of 50) still had this therapy prescribed at study completion compared with 48.6% (17 of 35) and 26.9% (7 of 26) of those who used anti-IgE and anti-IL-5 and anti-IL-5 receptor alpha (anti-IL-5/IL-5Rα) therapy, respectively. Among those on anti-IL-4Rα therapy, there was a significant reduction in median total 22-item sino-nasal outcome test scores (51 to 19, P= .0002), corticosteroid bursts (2 to 0, P < .0001), and median number of antibiotic courses for respiratory disease (1 to 0, P= .0469) prebiologic versus postbiologic initiation. No statistically significant difference in those outcomes was observed for individuals on anti-IgE or anti-IL-5/IL-5Rα therapy. Anti-IL-4Rα therapy led to significantly higher rates of clinical improvement in AERD when compared with anti-IL-5/IL-5Rα and anti-IgE biologic therapies. Prospective studies would help clarify best practices for the use of biologic therapies in AERD.