Cocoa beans have historically been used as a treatment for diarrhea, leading us to hypothesize that polyphenols contained in cocoa inhibit intestinal Cl- secretion. In this study, the dose-dependent effects of flavonoid compounds present in cocoa, or molecularly closely related compounds, were tested on forskolin-stimulated cystic fibrosis transmembrane conductance regulator (CFTR)-mediated Cl- secretion across T84 colonic epithelia in Ussing chambers. Addition of cocoa extract or cocoa flavanols to the mucosal side of tissues caused partial inhibition following Michaelis-Menten kinetics and resulted in a rank order of maximum blocker effects as follows: epicatechin > catechin > or = standardized cocoa preparation > or = procyanidin B2. Half-maximal blocker concentrations (Ki) were not substantially different between the tested preparations and were in the range of 100 micromol/L. For comparison, the structurally related flavonoids, quercetin and luteolin, caused a total block of Cl- currents with Ki values similar to the cocoa flavanols tested. Morin and baicalein were less effective blockers. Effects of test compounds on mucosal redox potential did not correlate with blocker activity. These data indicate that cocoa flavanols target intestinal CFTR Cl- transport and may serve as mild inhibitors of cAMP-stimulated Cl- secretion in the intestine.