Insulin-like growth factor binding proteins (IGFBPs) are a family of structurally homologous proteins that bind insulin-like growth factors (IGFs) with high affinities and can modulate IGF activity. The IGF binding site has been shown to comprise residues in both the aminoterminal and carboxyterminal domains. In recent years, several proteins including members of the CCN (CTGF, Cyr61 and Nov) family were recognized as having structural homology in their aminoterminal domains to the IGFBPs. In spite of their low or undetectable IGF binding ability, a proposal was made to rename them as IGFBP-related proteins. To test if the aminoterminal domain of a CCN protein can fulfil the high affinity IGF binding function of an IGFBP, we created a chimera in which the aminoterminal domain of IGFBP-3 was substituted with the aminoterminal domain of CCN3 (previously known as Nov). The CCN3-IGFBP-3 chimera bound IGFs and inhibited IGF activity very weakly, similar to CCN3 itself. Although structurally similar, the aminoterminal domain of CCN3 is unable to replace the aminoterminal domain of IGFBP-3 in forming a high-affinity IGF-binding site. These results argue against a direct role of CCN3 in the regulation of IGF bioavailability and indicate that the nomenclature of IGFBP-related proteins (which implies functional relationship to the classical IGFBPs) is inappropriate for CCN proteins.