Objective/Hypothesis: Therapeutic agents that enhance mucociliary transport (via stimulation of transepithelial Cl-secretion) and inhibit inflammation could provide considerable advantages over conventional treatments for chronic rhinosinusitis (CRS). The objectives of the present study were to investigate whether the polyphenolic compound resveratrol promotes transepithelial Cl- transport and inhibits KC/IL-8 secretion in sinonasal epithelium. Study Design: In vitro and in vivo study. Methods: Transepithelial Cl- transport was investigated in primary murine nasal septal (MNSE) and human sinonasal epithelial (HSNE) cultures. In vivo activity was also measured using the murine nasal potential difference assay. CFTR R-domain phosphorylation and cAMP levels were examined as a test of cAMP/PKA-dependent activation. In vitro LPS-induced KC/ IL-8 secretion was quantified and compared to a panel of intranasal steroids. Results: Resveratrol(100 μM) significantly increased CFTR-mediated Cl- transport (change in short-circuit current, DISC) in both MNSE (13.51 ± 0.77 vs. 4.4 ± 0.66 [control]; P < .05) and HSNE (12.28 ± 1.08 vs. 0.69 ± 0.32 [control]; P < .05). Cl- secretion across in vivo murine nasal epithelium was also enhanced (-4 ∓ 1.8 vs. -0.8 ± 1.7mV [control], P < .05). There was no increase in cellular cAMP or CFTR R-domain phosphorylation detected. Resveratrol also significantly inhibited KC/IL-8 secretion in a dose-dependent fashion (pg/mL) in MNSE (181 ± 39[100 μM) vs. 94 ± 16 [200 μM] vs. 16 ± 22 [500 μM] vs. 1195 ± 355 [LPS control]; P < .001). The compound robustly abrogated KC/IL-8 secretion when compared to ciclesonide (765 ± 139), triamcinolone (561 ± 124), and budesonide (742 ± 428), but had similar activity to fluticasone proprionate (65 ± 47). Similar effects were demonstrated in HSNE (975 ± 244 [100 μM] vs. 1825 ± 144 [LPS control]; P < .001) with inhibition comparable to fluticasone proprionate (785 ± 277). Conclusions: These in vitro and in vivo findings indicate resveratrol is a potent Cl- secretagogue and anti-inflammatory agent. Future clinical trials for CRS are warranted. © 2011 The American Laryngological, Rhinological and Otological Society, Inc.