3D-QSAR studies namely CoMFA, CoMFA region focusing and CoMSIA have been carried out on a series (36 compounds) of HIV-1 entry inhibitors. An alignment rule for the compounds was defined using Distill in SYBYL® 7.3. Models were validated using a data set obtained by dividing the data set into a training set and test set using hierarchical clustering, based on the CoMFA fields and biological activities (pIC50). The best predictions were obtained with a CoMFA region-focusing model (q2 = 0.719, rpred2 = 0.911), CoMFA standard model (q2 = 0.660, rpred2 = 0.890), and CoMSIA (steric and hydrophobic) model (q2 = 0.521, rpred2 = 0.794). The statistical parameters from the models indicate that the data are well fitted and have high predictive ability. Moreover, the resulting 3D CoMFA/CoMSIA contour maps provide useful guidance for designing highly active inhibitors.