The CC Chemokine Receptor 1 (CCR1) is closely related to various chronic inflammatory diseases like rheumatoid arthritis and multiple sclerosis, and plays a crucial role in transplant rejection. Inhibiting its activity with CCR1 antagonists has been proved to be effective in preventing some diseases. A number of in vivo experiments have been carried out to shed light on the underlying mechanism of the interactions between the CCR1 and its ligands. However, their conclusions are still controversial. In this study, ligand-based computational drug design is applied as a new and effective way to study the structure-activity relationship of CCR1 antagonists. Three-dimensional pharmacophore models were generated for CCR1 antagonists, using both HypoGen and HipHop algorithms in Catalyst software. Two optimal pharmacophore models were defined through careful qualification processes. Both of them have four features: one hydrogen-bond acceptor, one positive ionable and two hydrophobic groups. Additional information was obtained through comparison between the two models. Our results can be valuable tools for the discovery and development of specific, highly potent CCR1 antagonists. For Supplement material, please see the online version of the article. For Supplement material, please see the online version of the article.