The multidomain organization of SCO-spondin protein is a special feature of the chordate phylum. This protein is expressed in the central nervous system (CNS) from the time a dorsal neural tube appears in the course of phylogenetical evolution. With the advance of the systematic whole genomes sequencing, we were able to determine the SCO-spondin amino acid sequence in four mammalian species using the Wise2 software. From the ClustalW alignment of bovine (Bos taurus), human (Homo sapiens), murine (Mus musculus) and rat (Rattus norvegicus) proteins, a consensus sequence for mammalian SCO-spondin was determined and further validated with the dog (Canis familiaris) SCO-spondin sequence. The analysis of this consensus sequence is consistent with a very high degree of conservation in the amino acids composition and multidomain organization of SCO-spondin in mammals. In addition, the identification of conserved domains, namely, Emilin (EMI), von Willebrand factor D (vWD), low-density lipoprotein receptor type A (LDLrA) domains, SCO repeats (SCOR), thrombospondin type 1 repeats (TSR), a coagulation factor 5/8 type C (FA5-8C) or discoidin motif and a C-terminal cystine knot (CTCK) domain, provides a greater insight into the putative function of this multidomain protein. SCO-spondin belongs to the TSR superfamily given the presence of a great number of TSR (26). A finer classification of the TSR motifs in groups 1, 2 and 3 is proposed on the basis of different cysteine patterns. Interestingly, group 2 TSR are present in a number of CNS developmental proteins including R-spondins, F-spondins and Mindins.