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A 3D-QSAR study was conducted to analyze the anti-tumor activity (pHs,s =1,6) of dihydropyridin-2-one containing histone deacetylase inhibitor (DHDACi) to histone deacetylase (HDACs,s =1,6) by the comparative molecular field analysis (CoMFA) method.The predicting model was established based on the training set of 22 compounds,which was verified by the test set of 6 compounds containing template molecule.The results showed that the contributions of steric and electrostatic fields to pH1 are 37.6％ and 62.4％,and those to pH6 are 44.6％ and 55.4％,respectively.The coefficients of the cross-validation (Rcv2) and the non cross-validation (R2) are 0.574 and 0.947 for pH1,and 0.488 and 0.884 for pH6,respectively.The models were then used to predict the activities of the compounds for the training and testing sets.The results indicated that the models had strong stability and good predictability.Based on the 3D contour maps,several new potential inhibitors with higher anti-tumor activity were designed.However,the effectiveness of these potential inhibitors is still needed to be verified by the experimental results.