© American Academy of Otolaryngology-Head and Neck Surgery Foundation 2015. Objectives. Salubrious effects of the green coffee bean are purportedly secondary to high concentrations of chlorogenic acid. Chlorogenic acid has a molecular structure similar to bioflavonoids that activate transepithelial Cl transport in sinonasal epithelia. In contrast to flavonoids, the drug is freely soluble in water. The objective of this study is to evaluate the Cl secretory capability of chlorogenic acid and its potential as a therapeutic activator of mucus clearance in sinus disease. Study Design. Basic research. Setting. Laboratory. Subjects and Methods. Chlorogenic acid was tested on primary murine nasal septal epithelial (MNSE) (CFTR+/+ and transgenic CFTR/) and human sinonasal epithelial (HSNE) (CFTR+/+ and F508del/F508del) cultures under pharmacologic conditions in Ussing chambers to evaluate effects on transepithelial Cl transport. Cellular cyclic adenosine monophosphate (cAMP), phosphorylation of the CFTR regulatory domain (R-D), and CFTR mRNA transcription were also measured. Results. Chlorogenic acid stimulated transepithelial Cl secretion (change in short-circuit current [δISC = mA/cm2]) in MNSE (13.1 ± 0.9 vs 0.1 ± 0.1; P<.05) and HSNE (34.3 ± 0.9 vs 0.0 ± 0.1; P<.05). The drug had a long duration until peak effect at 15 to 30 minutes after application. Significant inhibition with INH-172 as well as absent stimulation in cultures lacking functional CFTR suggest effects are dependent on CFTR-mediated pathways. However, the absence of elevated cellular cAMP and phosphorylation the CFTR R-D indicates chlorogenic acid does not work through a PKA-dependent mechanism. Conclusion. Chlorogenic acid is a water-soluble agent that promotes CFTR-mediated Cl transport in mouse and human sinonasal epithelium. Translating activators of mucociliary transport to clinical use provides a new therapeutic approach to sinus disease. Further in vivo evaluation is planned.