Cutaneous neurofibromas consist of heterogenous cell populations including Schwann cells, perineurial cells, and fibroblastlike cells. However, the histogenesis of neurofibromas, particularly the origin and nature of the fibroblastlike cells, is still controversial. Recently, cells containing blood coagulation factor XIIIa have been reported in cutaneous neurofibromas, although their identity is uncertain. In this report, by the combination of double immunohistochemical straining and immunoelectron microscopy, we demonstrate that factor-XIIIa-positive cells are distinct from Schwann cells, perineurial cells, endothelial cells, mast cells, and conventional macrophages, but correspond to the fibroblastlike cells in cutaneous neurofibromas. Such factor-XIIIa-positive cells in cutaneous neurofibromas, however, differ from conventional fibroblasts in the strong expression of HLA-DR antigen and lack of prolyl 4-hydroxylase. Similarly, so-called endoneurial fibroblasts and, occasionally, connective tissue cells within perineurium and epineurium in normal peripheral nerve fibers express factor XIIIa as well as HLA-DR antigen. The results suggest that fibro-blastlike cells in cutaneous neurofibromas are probably derived from factor-XIIIa- and HLA-DR antigen-positive connective tissue cells in peripheral nerves. The role of such factor-XIIIa-positive cells in the growth and development of cutaneous neurofibromas is discussed.