Anti-HIV (human immunodeficiency virus) drug discovery has been increasingly focusing on HIV integrase (IN) as a potential therapeutic target. This enzyme is required for the integration of reverse transcribed proviral DNA into the host cell's genome and is essential for the propagation of the HIV life cycle. Comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) three-dimensional quantitative structure-activity relationship (3D QSAR) studies and docking simulations were conducted on a series of potent conformationally restrained cinnamoyl inhibitors of HIV-1 IN (Artico; et al. J. Med. Chem. 1998, 41, 3948-3960). Predictive 3D QSAR models were established using SYBYL multifit molecular alignment rule, which had conventional r(2) and cross-validated coeffiecient (q(2)) values up to 0.981 and 0.721 for CoMFA and 0.975 and 0.804 for CoMSIA, respectively. These models were validated by an external test set (Burke; et al. J. Med. Chem. 1995, 38, 4171-4178). CoMFA and CoMSIA 3D QSAR models were also derived using a molecular alignment obtained by docking the compounds into the active site of HIV IN. These latter models were comparable to multifit-derived models in terms of relative descriptor field contributions and the partial least squares (PLS) contour maps. The CoMSIA 3D QSAR models performed better than the CoMFA models. The superior performance of CoMSIA was attributed to the large contribution of hydrogen-bonding interactions to the inhibitory activity differences among the compounds. This was supported by FlexX binding energy scores that correlated well with the inhibitory activity differences between hydroxylated compounds and their corresponding methoxy or deoxy counterparts. The CoMFA and CoMSIA PLS contour maps and MOLCAD-generated active site electrostatic, lipophilicity, and hydrogen-bonding potential surface maps, as well as the docking results, were integrated to propose a binding mode for the cinnamoyl inhibitors at the active site of HIV-1 IN.