Recent evidence in animal models suggests that components of the extracellular matrix (ECM) play a primary role in peripheral nerve degeneration and regeneration. We investigated the expression of several ECM molecules in human sural nerves by immunohistochemistry, Western blot, and reverse transcriptase PCR analysis. To unravel the possible role of these molecules in nerve regeneration, we compared results obtained from nerves with abundant signs of regeneration with those with complete absence of axonal regeneration. The role of some ECM components on neurite extension was further tested in dorsal root ganglion cultures. We observed that the ECM composition significantly differs in regenerating compared with nonregenerating nerves, independently from their etiologic background. Fibronectin was abundantly expressed in regenerating nerves, whereas vitronectin and fibrin(ogen) prevailed in nonregenerating nerves. Whereas fibronectin is secreted by endoneurial cells, in vivo and vitro studies showed that the source of vitronectin and fibrin(ogen) is the bloodstream. These data indicate that nerve regeneration is impaired in the presence of breaches in the blood-nerve barrier or impaired extracellular matrix (ECM) degradation that leads to accumulation of plasma vitronectin and fibrin(ogen). The transformation into mature, fibronectin-enriched ECM is necessary for efficient nerve regeneration in humans.