The two-dimensional Quantitative Structure-Activity Relationship (2D-QSAR) models have been developed to estimate and predict the inhibitory activities of a series of HEPT analogues against HIV-1 by using quantum chemical parameters and physicochemical parameters. The best model of three parameters yields r = 0.908, r2A = 0.800 and s = 0.467 based on stepwise multiple regression (SMR) method. The stability of the model has been verified by t-test, and the results show that the model has perfect robustness. The predictive power of QSAR models has been tested by Leave-One-Out (LOO) and Leave-Group(regularly random set)-Out(LGO) procedure Cross-Validation methodology. The r2CV of 0.755 and r2pred of 0.759 were obtained, respectively.