Aims To identify active phenolic constituents in muscadine grape skin (MGS) extracts and determine interactions among compounds while further exploring their anti-Helicobacter pylori potential in vitro. Methods and Results The inhibitory effects of quercetin and resveratrol, active polyphenols identified in MGS extracts, against H.pylori were investigated. Quercetin and resveratrol significantly (P<0 center dot 05) reduced H.pylori counts regardless of pH with minimal bactericidal concentrations of 256 and 128gml1, respectively. MGS extracts displayed the highest efficacy, suggesting additional unidentified compounds not determined in this study. Time-course viability experiments showed a dose-dependent anti-H.pylori response to quercetin and resveratrol. Interestingly, neither quercetin nor resveratrol affected H.pylori outer membrane (OM) integrity as determined by 1-N-phenylnaphthylamine (NPN) uptake assays. However, treatment with MGS extract did increase NPN uptake, indicating OM destabilization possibly by additional unknown components. Furthermore, quercetin was found to enter H.pylori as measured by HPLC supporting intracellular drug accumulation. Conclusions Quercetin and resveratrol possess strong anti-H.pylori activity in vitro and are independent of pH. Our results also suggest that these compounds do not affect H.pylori OM integrity as previously hypothesized and that the primary antimicrobial activity of quercetin may be linked to interactions with intracellular components. Significance and Impact of the Study The anti-H.pylori effects of quercetin and resveratrol suggest that these compounds may be useful in the dietary prevention and/or treatment of H.pylori infection.