Background Chronic rhinosinusitis (CRS) may cover different disease entities, and the pathogenic mechanism remains unclear. Methods The aim of this study was to evaluate the expression of chloride channel protein CLC-2 and CLC-3 in CRS without nasal polyps (CRSsNP) and evaluate the roles of interleukin (IL)-4 and transforming growth factor (TGF) beta in the up-regulation of CLC-2 and CLC-3. We detected expression of CLC-2 and CLC-3 in 17 patients with CRSsNP by immunohistochemistry and reverse transcription-polymerase chain reaction (RT-PCR), and we examined the concentration of TGF-beta, IL-4, IL-5, and interferon (IFN) γ in ethmoid sinus mucosa by enzyme-linked immunosorbent assay (ELISA). Results We found that CLC-2 and CLC-3 is up-regulated in CRSnNP and located in submucosal glands and epithelium of the ethmoid sinus. CLC-2 and CLC-3 mRNA correlated with IL-4 in CRSsNP (r = 0.57 and 0.65; p < 0.05). CLC-2 and CLC-3 mRNA correlated negatively with mucosal TGF-beta in CRSsNP (r = -0.49 and -0.54; p < 0.05). Conclusion We concluded that CLC-2 and CLC-3 is up-regulated in ethmoid mucosa and may affect the development of CRSsNP. TGF-beta and IL-4 may modulate the expression of CLC-2 and CLC-3 in CRSsNP.