BACKGROUND: In addition to known concerns regarding antibiotic overuse, recent research indicates that excessive antibiotic use is associated with poorer long-term health. Given that rhinosinusitis is the leading condition accounting for antibiotic prescriptions in the ambulatory setting, we aimed to evaluate characteristics associated with greater antibiotic use in chronic rhinosinusitis (CRS). METHODS: Adult CRS patients enrolled in a prospective, multi-institutional, observational cohort study evaluating treatment outcomes were included in this analysis. Study participants were asked to report the number of days out of the previous 90 days that systemic antibiotics were taken for sinus disease. Patient demographics, disease characteristics, and measures of disease severity were evaluated. RESULTS: A total of 561 patients from 4 institutions were included in the analysis, with mean antibiotic use of 17.4 ± 22.4 out of the prior 90 days. No differences between antibiotic-use groups were found for objective measures of disease severity (computed tomography [CT], endoscopy, Brief Smell Identification Test [BSIT] scores), however, increased patient-reported symptom burden (22-item Sino-Nasal Outcome Test [SNOT-22], Rhinosinusitis Disability Index [RSDI]) was associated with more antibiotic use. Patients reporting the most antibiotic use were older (p = 0.004) but no ethnic or gender differences were seen. Comorbid diagnoses of allergy, asthma, diabetes, depression, or fibromyalgia were not associated with increased antibiotic use. In accordance with literature recommendations, CRS with nasal polyps (CRSwNP) patients were less likely to have used antibiotics. Endoscopic sinus surgery (ESS) significantly decreased antibiotic use. CONCLUSION: Variability in antibiotic use in CRS appears to be driven by symptom burden, independent of objective measures of disease severity, patient demographics, and presence of comorbid disease. Clear guidelines are essential to define appropriate antibiotic use in CRS.