Resveratrol has been examined in several model systems for potential effects against cancer. Adenosinemonophosphate-activated protein kinase (AMPK) is reported to suppress proliferation in most eukaryocytecells. Whether resveratrol via AMPK inhibits proliferation of oesophageal adenocarcinoma cells (OAC) isunknown. The aim of this study was to determine the roles of AMPK in the protective effects of resveratrol inOAC proliferation and to elucidate the underlying mechanisms. Treatment of cultured OAC derived from humansubjects or cell lines with resveratrol resulted in decreased cell proliferation. Further, inhibition of AMPK bypharmacological reagent or genetical approach abolished resveratrol-suppressed OAC proliferation, reduced thelevel of p27Kip1, a cyclin-dependent kinase inhibitor, and increased the levels of S-phase kinase-associated protein2 (Skp2) of p27Kip1-E3 ubiquitin ligase and 26S proteasome activity reduced by resveratrol. Furthermore, genesilencing of p27Kip1 reversed resveratrol-suppressed OAC proliferation. In conclusion, these findings indicatethat resveratrol inhibits Skp2–mediated ubiquitylation and 26S proteasome-dependent degradation of p27Kip1via AMPK activation to suppress OAC proliferation.