Dynamic mutations of simple sequence repeats (SSRs) have been demonstrated to affect normal gene function and cause different genetic disorders. Several conserved and even partial functional SSR patts are discovered in inherited orthologous disease genes. To explore a wide range of SSRs in genetic diseases, a comprehensive system focusing on identifying orthologous SSRs of disease genes through a comparative genomics mechanism is constructed and accomplished by adopting online Mendelian inheritance in man (OMIM) and NCBI HomoloGene databases as the fundamental resources of human genetic diseases and homologous gene information. In addition, an efficient and effective algorithm for searching SSR patts is also developed for providing annotated SSR information among various model species. By integrating these data resources and mining technologies, biologists and doctors can systematically retrieve novel and important conserved SSR information among orthologous disease genes. The proposed system, Orthologous SSR for Disease Genes (OSDG), is the first comprehensive framework for identifying orthologous SSRs as potential causative factors of genetic disorders and is freely available at http://osdg.cs.ntou.edu.tw/.