In this study, we utilized comparative molecular field analysis (CoMFA) to gain a better understanding of the steric and electrostatic features of the cytochrome p450 2D6 (CYP2D6) active site. The training set consists of 24 substrates with reported K(M) values from liver microsomal CYP2D6 spanning an activity range of almost three log units. The low energy conformers were fit by root mean square (RMS) to minaprine at the site of metabolism and to the protonated nitrogen. In this manner, we constructed two CoMFA models, one model with a distance constraint and another without. The model with the distance parameter (non-cross-validated R(2)=0.99) was approximately equal to the CoMFA without a distance parameter (non-cross-validated R(2)=0.98). Validation of our CoMFA was accomplished by predicting the K(M) values of 15 diverse CYP2D6 substrates not in the original training set resulting in a predictive R(2)=0.62. Finally, we also pursued correlations of pK(a) and log P with CYP2D6 substrate K(M) in an effort to investigate other physicochemical properties.