We conducted a prospective study of 586 adults to determine if associations exist between fatigue symptom scores and three classes of medications prescribed for the treatment of chronic rhinosinusitis (CRS): prescription nonsedating antihistamines, topical nasal steroids, and antibiotics. Patients were assessed with the assistance of the Rhinosinusitis Symptom Inventory and Likert-scale fatigue symptom scores. On multivariate analysis and correcting for disease severity, we found that significantly higher fatigue symptom scores were associated with the use of nonsedating antihistamines (mean Likert score: 2.75 vs. 2.27 for patients not taking a nonsedating antihistamine; p = 0.029). Higher fatigue scores were also associated with a greater number of antibiotic courses and more total weeks of antibiotic use (p < 0.001 in both cases). No association was seen between fatigue scores and the use of topical nasal steroids (mean Likert score: 2.65 vs. 2.24; p = 0.658). We recommend that long-term use of a nonsedating antihistamine be scrutinized in CRS patients who report symptoms of fatigue.