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Jia-Suo Gao,1* Xu-Peng Tong,2* Yi-Qun Chang,1 Yu-Xuan He,1 Yu-Dan Mei,1 Pei-Hong Tan,1 Jia-Liang Guo,1 Guo-Chao Liao,3 Gao-Keng Xiao,1 Wei-Min Chen,1 Shu-Feng Zhou,4 Ping-Hua Sun1 1Guangdong Province Key Laboratory of Pharmacodynamic Constituents of Traditional Chinese Medicine and New Drugs Research, College of Pharmacy, Jinan University, Guangzhou, People’s Republic of China; 2College of Pharmacy, China Pharmaceutical University, Nanjing, People’s Republic of China; 3Department of Chemistry, Wayne State University, Detroit, Michigan, USA; 4College of Pharmacy, University of South Florida, Tampa, FL, USA *These authors contributed equally to this work Abstract: Factor IXa (FIXa), a blood coagulation factor, is specifically inhibited at the initiation stage of the coagulation cascade, promising an excellent approach for developing selective and safe anticoagulants. Eighty-four amidinobenzothiophene antithrombotic derivatives targeting FIXa were selected to establish three-dimensional quantitative structure–activity relationship (3D-QSAR) and three-dimensional quantitative structure–selectivity relationship (3D-QSSR) models using comparative molecular field analysis and comparative similarity indices analysis methods. Internal and external cross-validation techniques were investigated as well as region focusing and bootstrapping. The satisfactory q2 values of 0.753 and 0.770, and r2 values of 0.940 and 0.965 for 3D-QSAR and 3D-QSSR, respectively, indicated that the models are available to predict both the inhibitory activity and selectivity on FIXa against Factor Xa, the activated status of Factor X. This work revealed that the steric, hydrophobic, and H-bond factors should appropriately be taken into account in future rational design, especially the modifications at the 2'-position of the benzene and the 6-position of the benzothiophene in the R group, providing helpful clues to design more active and selective FIXa inhibitors for the treatment of thrombosis. On the basis of the three-dimensional quantitative structure–property relationships, 16 new potent molecules have been designed and are predicted to be more active and selective than Compound 33, which has the best activity as reported in the literature. Keywords: CoMFA, CoMSIA, 3D-QSAR, 3D-QSSR, benzothiophene antithrombosis