Chronic rhinosinusitis (CRS) is one of the most common chronic disorders of the upper airways that is frequently observed in patients with cystic fibrosis (CF), a rare genetic disease caused by abnormal epithelial ion transport. CRS is a heterogeneous disease which may be linked to impaired mucociliary clearance and sinonasal inflammation. However, other underlying CRS pathophysiologic mechanisms still remain unspotted. Here, we aimed to study whether the epithelial ion transport, in particular the Ca2+-mediated Cl- secretion is affected in patients with CRS. We further determined the epithelial expression of cytokines being both, associated with Cl- transport and implicated in CRS. First, cultured nasal epithelial primary cells of healthy individuals (n=10-20) and CRS patients (n=10-22) were utilized to study epithelial ion transport and transcript levels of the Ca2+-activated Cl- channel TMEM16A and CFTR. Levels of cytokines were also assessed (IFN-γ, IL-13, IL1-β). Effects of IL-13 on gene expression and epithelial Cl- transport were investigated. Second, nasal potential difference (NPD) measurements were carried out in healthy individuals (n=16) and CRS patients (n=8). Results, expressed as mean±SEM were compared by ANOVA. Bioelectric studies revealed significantly reduced basal short-circuit current (Isc) and Ca2+-activated Cl- secretory responses (p<0.05), albeit mRNA levels of the Ca2+-activated Cl- channel TMEM16A were significantly increased (Control: 1.0±0.2 vs. CRS: 2.0±0.3, p<0.01). MRNA and protein expression of the Th2-inflammation marker IL-13 were strongly increased in CRS cultures. Whilst mRNA and protein expression levels of the Th1-inflammation marker IL1-β were significantly decreased (protein: Control: 19.5±9.7 vs. CRS: 0.2±0.1, p<0.05). By acute treatment with IL-13, Ca2+-activated Cl- secretion by means of UTP-mediated Isc can be partially restored in CRS cultures (untreated: 0.3±0.1 vs. IL-13 treatment: 1.8±0.5, p<0.05). Levels of TMEM16A expression were also further increased by 3-fold (p<0.05). In vivo nasal PD measurements confirmed a significant reduction of Ca2+-activated Cl- secretion in CRS patients compared to healthy individuals (p<0.05). Our data suggest a complex dysregulation of epithelial Cl- transport dominated by reduced basal Isc values and Ca2+-activated Cl- secretion in nasal epithelia of CRS patients. Changes in Ca2+-activated Cl- secretion were further confirmed in vivo by NPD measurement. The epithelial inflammation in CRS cultures is also significantly evident in the signature of cytokines being implicated in epithelial Cl- transport. These data indicate that TMEM16A-mediated Cl- secretion may play an important role in the pathogenesis and TMEM16A may serve as a therapeutic target in CRS.