Abstract: The electronic structures, geometric structures and some molecular properties (generalized structural indexes) of quinazoline derivatives were computed by using density functional theory and molecular mechanism methods to investigate the quantitative structure-activity relationship (QSAR) of the inhibitory activity toward the nuclear factor kappa B. Via a stepwise regression analysis, some main factors affecting the activity of the compounds were factored out, and then the QSAR equation was effectively established. It was found that the hydrophobic parameter of the substituent on ring D is the main factor affecting the inhibitory activity of the compound. The analysis indicated, the larger the hydrophobic parameter, the higher the inhibitory activity of the compound. In addition, the net charge of the first atom and the stereoscopic parameter (MR1) of the substituent R1 on A-ring as well as the net charge of C3 are closely correlated with the inhibitory activity of the compound. In order to test the predicted results of the QSAR equation, we adopted the “leave one out” cross-validation , and found that the calculated coefficient q2 was rather high and the predicted results were both accurate and reliable. Such facts show that the obtained equation has great predictive ability. The above results can offer an important theoretical guide in the search for new quinazoline derivatives with higher inhibitory activity, and in an analysis of their action mechanisms. It is noteworthy that this scheme would be very advantageous in factoring out precursors with excellent inhibitory activity via the computer ADDIT molecule-design, since all parameters in the QSAR equation are computable and controllable.