Background and aims: Resveratrol, the most investigated dietary compound in studies aimed at linking wine consumption to human health, is an extremely minor component of this beverage and it is generally studied in vitro as the unconjugated aglycone at concentrations largely exceeding those found in the human circulatory system after dietary intake. Moreover, following intestinal absorption, trans-resveratrol and its glucoside, which are naturally present in wine and other food sources, are converted to sulfate and glucuronide metabolites. An estrogenic activity has previously been documented for resveratrol, yet nothing is known about the activity of its blood-circulating metabolic derivatives. Methods and Results: Using a yeast two-hybrid detection system relying on the interaction between the ligand-binding domain of the human estrogen receptors α and β and the human coactivator Tif2, we have systematically examined the estrogen agonist and antagonist activities of the two main resveratrol forms present in planta (trans-resveratrol and trans-resveratrol-3-O-glucoside) and of the three main metabolites found in human plasma (trans-resveratrol-3-O-sulfate, trans-resveratrol-3-Oglucuronide and trans-resveratrol-4’-O-glucuronide). Only resveratrol-3-O-sulfate was found to display a fairly strong and estrogen receptor α-preferential antagonistic activity, which was confirmed in a human breast adenocarcinoma cell line containing a luciferase reporter gene under the control of an estrogen-responsive promoter. Conclusions: We show, for the first time, that resveratrol-3-O-sulfate, but neither of its metabolites, is endowed with anti-estrogenic activity and how human metabolism of phenolic substances plays a pivotal role in modulating their biological effect.