There is considerable evidence that stilbenes provide health benefits. trans-Polydatin is one of the major stilbenoid compounds in red wine. The purpose of this study is to investigate the dose-dependent absorption and metabolism of trans-polydatin in rats. trans-Polydatin was administered to rats by gavage at three different doses (50, 100, and 300 mg x kg(-1)). Blood samples were then collected at different time points. In situ perfusion of rat small intestine and liver was used to investigate the first-pass metabolism of trans-polydatin. trans-Polydatin and its metabolites were detected by LC-MS/MS. trans-Polydatin and its metabolites resveratrol, glucuronidated resveratrol, and glucuronidated trans-polydatin were detected in plasma within 10 min following oral administration of trans-polydatin; in situ perfusion of the rat small intestine and liver with trans-polydatin yielded the same result. The AUC(0-infinity) of trans-polydatin and its metabolites increased in a dose dependent manner following oral administration of trans-polydatin. This indicates that in the rats, trans-polydatin is absorbed in a dose-dependent manner and undergoes extensive first-pass deglycosylation and glucuronidation. Orally administered trans-polydatin, therefore, is metabolized primarily to resveratrol in the small intestine and liver, where it is further metabolized to the glucuronidated resveratrol.