CIKS (TRAF3IP2/Act1) is important for inflammatory responses and autoimmunity control through its dual functions in CD40L/BAFF and IL17 signaling in mammalians. In this study, we performed comparative and evolutionary analyses of CIKSs from metazoans. Although nematode (Caenorabditis elegans) and sea urchin (Strongylocentrotus purpuratus) have IL17 and IL17 receptors, we found no CIKS in their genomes. The ancient CIKS-like (CIKSL) genes from the invertebrates lottia (Lottia gigantea) and amphioxus (Branchiostoma floridae) have an additional DEATH domain compared with other CIKSLs/CIKSs. Our data suggest that the ancient CIKSL evolved into early chordate CIKS possibly through gene tandem duplication and gene fission. Based on phylogenetic and synteny analyses, vertebrate CIKS genes are divided into two groups, one of which is orthologous to human CIKS and the other is paralogous. Expression analysis indicated that cephalochordata amphioxus IL17 together with CIKS might play an ancient and conserved role in host defense against bacterial infections. During the evolutionary process, the CIKS genes have obtained more and more functions through cooperation with other genes.