A comparative molecular similarity index analysis (CoMSiA) has been performed for cytochrome P450 2D6 inhibition on a series of aryloxypropanolamines to determine the factors contributing to this activity. The model is in agreement with a CYP2D6 homology model constructed on the basis of the mammalian CYP2C5 crystal structure. The energy minimized conformations were generated using the systematic search methodology in Sybyl 6.7. The model not only elucidated the relationship between structure and biological activity but, more importantly, provided useful strategies to modulate CYP2D6 affinity in the aryloxypropanolamine series.