Background: Allergic rhinitis (AR) and chronic rhinosinusitis (CRS) are common airway diseases worldwide. AR and CRS frequently occur together in a patient, and they share some similar pathological mechanisms. The aim of this study was to investigate the impact of AR on the pathophysiology of CRS. In addition, we explored the efficacy of erythromycin (EM) treatment on experimental CRS mice with or without AR (CRSsAR, CRSwAR). Methods: Patient nasal tissues were obtained from those underwent nasal surgery. Subjects were divided into three groups: control, CRSsAR, and CRSwAR groups. Experimental mice were divided similarly into control, CRSsAR, and CRSwAR groups. In addition, CRSsAR and CRSwAR mice were treated with EM at 0.75, 7.5, or 75mg/kg or with dexamethasone (Dex) at 1mg/kg. Results: Allergy exacerbates nasal inflammation that was evident in nasal histology and cytokine expressions both in patients and in mice with CRS. Dex 1 mg/kg, EM 7.5 or 75 mg/kg treatments all effectively inhibited nasal inflammation in mice. EM reduced serum immunoglobulin levels, inhibited mucosal mucus production, and modulated local cytokine expressions in CRS mice with or without AR. Anti-inflammatory mechanisms of EM and of Dex did not appear to be the same. EM showed inhibitions on immunoglobulin production and mucus secretion stronger than Dex. Dex broadly reduced cytokine expressions whereas EM had an immunomodulatory effect on Th1/Th2 cytokine expressions. Conclusions: Comorbid AR enhanced sinonasal inflammation of CRS. EM and Dex treatments showed similar anti-inflammatory effects on CRS but through partly different mechanisms.