The cellular heterogeneity of cutaneous tumors from nine patients with type 1 (von Recklinghausen's) neurofibromatosis was studied using several antigenic markers with special reference to focal heterotopic differentiation and interindividual variation. Furthermore, cells which actively express the genes for type I and III collagens and fibronectin, the major components of the abundant extracellular matrix of neurofibromas, were localized using in situ hybridizations. In eight of nine cases, the S-100 protein positive cells, i.e. Schwann-like cells, composed 60 to 80% of the total cell population. However, in one case, only about 40% of the cells were S-100 protein positive. The latter tumor was studied with respect to perineurial cell differentiation and stained with a mixture of two antibodies, directed against the S-100 protein and type IV collagen. In Schwann cells, the staining reaction for S-100 protein was observed in the nuclear region, whereas the staining reaction for type IV collagen was located peripherally, corresponding to the basement membrane zone covering the cells. The stromal cells which showed only the peripheral staining profile were considered to be neoplastic perineurial cells. Distinct structures with epithelial, endothelial, or smooth muscle cell differentiation were present within the benign tumors, as detected by immunostaining for cytokeratin, epithelial membrane antigen, factor VIII-related antigen and desmin, respectively. In situ hybridizations revealed a clearly detectable expression of type I procollagen genes in less than 10% and type III procollagen gene in less than 5% of the total cell population. Active synthesis of fibronectin was limited to the vascular walls, when examined by in situ hybridization, and antibodies to cellular fibronectin localized to the same areas. However, antibodies to plasma fibronectin produced a uniform staining reaction throughout the tumors suggesting that most of the fibronectin in neurofibromas is plasma-derived. The latter observation suggests that neurofibroma cells are freely accessible to various plasma proteins, including growth factors, which may influence the growth characteristics of these lesions.