The human melanoma-associated chondroitin sulfate proteoglycan (MCSP) and its rat ortholog NG2 are thought to play important roles in angiogenesis-dependent processes like wound healing and tumor growth. Based on electron microscopy studies, the highly glycosylated ectodomain of NG2 has been subdivided into the globular N-terminus, a flexible rod-like central region and a C-terminal portion in globular conformation. We identified a novel repeat named CSPG in the central ectodomain of NG2, MCSP and other proteins from fly, worm, human, sea urchin and a cyanobacterium which shows similarity to cadherin repeats. As earlier electron microscopy studies indicate, the folding of the tandem repeats compresses the length of the proposed repeat region by a factor of approximately 10 compared to the fully extended peptide chain. We identified two conserved negatively charged residues which might govern the binding properties of CSPG repeats. The phyletic distribution of CSPG repeats suggests that horizontal gene transfer contributed to their evolutionary history.