To compare the features of the active sites of CYP2C8, CYP2C9, and CYP2C19, homology modeling was performed based on the crystallographic coordinates of mammalian CYP2C5. It was found that CYP2C8 has a much larger pocket than the other forms due to the existence of an additional pocket. The approach to the additional pocket is comprised of Ile102, Ser114, Leu208, Val366, and Ile476, and the side chains of Ser114, Val366, and Ile476, which are smaller than the corresponding residues in the other CYPs, enable access to the pocket. The general features of the active site in the CYP2C8 model are similar to those of the previously constructed CYP3A4 model, which may account for the 2 CYPs sharing some of their substrates. The CYP2C8 model was validated by examining the bound orientation of paclitaxel and showing that it is consistent with the formation of the 6-beta hydroxylated derivative during metabolism. Docked paclitaxel was found to form a hydrogen bond with the side chain of Asn 99, which is a characteristic residue of CYP2C8 and is located in the additional pocket. Descriptors for CYP2C8 and CYP2C9 substrates were also examined with the molecular operating environment (MOE). The descriptor by which CYP2C8 and CYP2C9 substrates were classified most distinctly was found to be molar refractivity, which might be related to the longer shape and more polar nature of the active site of CYP2C8 in the CYP2C subfamily.