Abstract: The gp41 inhibitors were selected as targets to investigate the interactions between gp41 inhibitors and the structure of small molecules using topomer comparative molecular field analysis (CoMFA) methods. The small molecule inhibitors are chosen from the literatures, and the molecule model was constructed by using Topomer CoMFA. Then, the predicative ability of the model was analyzed according to the statistical method and an ideal prediction model is obtained. These results may give guidance in the future research including the activity prediction of the compounds, the structure modify of molecules, and drug design.