The suppressors of cytokine signaling (SOCS) family play important roles in regulating a variety of signal transduction pathways that are involved in immunity, growth and development of organisms. However, the family members in early vertebrate species and their evolutionary history and relationships remain largely unknown. In present study, totally 120 SOCS genes from various species were globally investigated, among of which 66 new SOCS genes were identified, including 55 SOCS genes from five fish species, Tetraodon nigroviridis, Danio rerio, Takifugu rubripes, Gasterosteus aculeatus and Oryzias latipes, 11 from amphibian, avian and insects. The results showed that fish possess at least 12 SOCS family members, including eight known mammalian SOCS members (CISH, SOCS-1-7) and four novel members (SOCS-3b, -5b, -8 and -9). Fish SOCS proteins share strikingly high levels of sequence similarity in SH2 domain and SOCS box region with higher vertebrate counterparts, and the organization of SOCS genes are conserved during vertebrate SOCS evolution. The expression levels of the most fish SOCS genes, such as CISH, SOCS-1-5 and SOCS-9, were increased after LPS challenge, indicating that they are involved in inflammatory response. Phylogenetic analyses clearly showed that the SOCS gene family could be divided into two subfamilies (named as types I and II subfamily). Type I subfamily consists of vertebrate SOCS-4-7, SOCS-5b, SOCS-9 and all invertebrate SOCS genes. Type II subfamily contains vertebrate CISH, SOCS-1-3, SOCS-3b and SOCS-8. Only SOCS-5, -6 and -7 like genes existed in invertebrate, which may be generated by twice-ancient duplication events. Type II subfamily members were likely derived from a certain type I member by gene duplication in the vertebrate lineages after the divergence of vertebrate from invertebrate. In type II subfamily, SOCS genes formed two separate monophyletic groups, respectively, which suggests that another duplication event occurred in the early stage of evolution. The fact that SOCS-9, SOCS-5b, SOCS-3b and SOCS-8 present only in teleostei suggests that even more duplication events occurred before teleostei and higher vertebrates diverged. Results suggest that the SOCS multi-gene family derived from the expansion of an ancestral SOCS gene through at least cubical duplication events during evolution process.