Cutaneous neurofibromas contain an extensive extracellular matrix composed of collagenous and non-collagenous macromolecules. In this study, the expression of type VI collagen genes in cutaneous neurofibromas was examined by a combination of in situ hybridizations and immunohistochemistry. In situ hybridizations with a 32P-labeled human type VI collagen-specific cDNA revealed that the majority of cells within neurofibromas expressed the gene for alpha 2(VI) collagen chain. The number of cells expressing clearly detectable levels of alpha 2(VI) collagen mRNA was considerably higher than that of cells actively expressing the pro alpha 1(I) or pro alpha 1(III) collagen genes. The presence of type VI collagen epitopes within the neurofibromas was also demonstrated by immunostaining with specific polyclonal antibodies. The expression of type VI collagen genes in neural tissues was further examined by immunostaining of a benign schwannoma tissue specimen consisting of Schwann cells. The results indicated close association of type VI collagen epitopes with the neoplastic Schwann cells. Immunolocalization of type VI collagen epitopes within normal human peripheral nerve revealed pericellular staining of perineurial cells and Schwann cells, suggesting synthesis of type VI collagen by these cell types. These results suggest that the expression of type VI collagen gene is active in nerve-derived tissues, and that type VI collagen may be a major component of the extracellular matrix in neural connective tissues.