The aim of the present study was to investigate the mechanism for the stereoselective presystemic clearance of carvedilol. We examined the oxidation and glucuronidation of carvedilol in human liver microsomes (HLM) and human intestinal microsomes (HIM). The oxidation of carvedilol in HLM and HIM was evaluated in the presence of NADPH, whereas glucuronidation was evaluated in the presence of UDP-glucuronic acid. Oxidation of S-carvedilol in HLM and HIM was greater than that of R-carvedilol. In addition, the oxidation of R-carvedilol in HLM was inhibited by quinidine, whereas that of S-carvedilol was inhibited by both quinidine and furafylline. On the other hand, R- and S-carvedilol oxidation in HIM was inhibited by ketoconazole. Glucuronidation of S-carvedilol in HLM and HIM was also higher than that of R-carvedilol. These results suggested that cytochrome P450 (CYP) 2D6 and CYP1A2 are involved in the stereoselective oxidation of carvedilol in the liver, that CYP3A4 is involved in intestinal oxidation, and that glucuronidation in the liver and intestine is at least partly responsible for stereoselective presystemic clearance.