The aim of the present study is to develop a method for predicting the site at which molecules will be metabolized by CYP 2C9 (cytochrome P450 2C9) using a previously reported protein homology model of the enzyme. Such a method would be of great help in designing new compounds with a better pharmacokinetic profile, or in designing prodrugs where the compound needs to be metabolized in order to become active. The methodology is based on a comparison between alignment-independent descriptors derived from GRID Molecular Interaction Fields for the CYP 2C9 active site, and a distance-based representation of the substrate. The predicted site of metabolism is reported as a ranking list of all the hydrogen atoms of each substrate molecule. Eighty-seven CYP 2C9-catalyzed oxidative reactions reported in the literature have been analyzed. In more than 90% of these cases, the hydrogen atom ranked at the first, second, or third position was the experimentally reported site of oxidation.