The activity of a set of anilide inhibitors of the Hill reaction was modeled using the traditional Hansch approach and Comparative Molecular Field Analysis (CoMFA). In the “best” Hansch model the most relevant parameters were the hydrophobic constants associated to substituents at the 3- and 4-positions of the benzene ring (π3and π4) and theB1Verloop's parameter describing the “minimum width” of the substituent attached to the carbonyl. Successively, a combined “Hansch–CoMFA” analysis was performed using as descriptors the steric field of the acyl substituents in conjunction with the π3and π4constants multiplied by proper weighting factors. The results of this latter type of analysis were significantly better than those obtained through the traditional Hansch approach. The predictive ability of the “Hansch–CoMFA” model was further tested by predicting the activity of a large number of anilides not included in the training set. The residuals of such predictions indicated that the Hansch–CoMFA model was characterized by higher predictive ability and confirmed the efficiency of such a 3D–QSAR method in handling shape-dependent factors.