Thirty six aryloxypropanolamine compounds with cytochrome 2D6 (CYP2D6) inhibitory activity were subjected to molecular shape analysis and molecular field analysis studies to explore the required molecular shape features as well as information on putative interactions with the active site of the enzyme. In addition to the 3D QSAR models, impact of two-dimensional (2D; thermodynamic, structural and topological including E-state parameters) descriptors towards the inhibitory activity was also studied. The whole data set was divided into training (n = 26) and test (n = 10) sets by K-means clustering technique. The chemometric tools used for molecular shape analysis and molecular field analysis were GFA and G/PLS techniques respectively. The G/PLS model derived in molecular field analysis using maximum common subgroup alignment was found to be the best model based on highest external (R(2)(pred) = 0.912) predictive power with lowest RMSEP value (0.363). The molecular field analysis-derived models suggest the requirement of U-shape conformation for optimum interactions as well as importance of different substituents on the aryloxypropanol fragment like indolylalkyl substituent. The molecular shape analysis models indicate the importance of distribution of positive and negative charges on the surface of the molecules. The QSAR models with 2D descriptors reveal the importance of bulk, branching and presence of different fragments.