Development of neurofibroma (NF) and its malignant counterpart, malignant peripheral nerve sheath tumor (MPNST), is a hallmark of type I neurofibromatosis (NF1). Newly identified glycoprotein neuronatin (Nnat) is predominantly expressed in the fetal central and peripheral nervous systems and is gradually diminished according to the neural maturation. However, its expression in NFs and MPNSTs is unknown. Since an overexpression of tenascin-C (Tn-C), an extracellular matrix component, has been observed in neural malignancies, we investigated the immunohistological expressions of Nnat and Tn-C in NFs and MPNSTs, and compared their expression with that of the proliferation marker Ki-67 to possibly distinguish MPNSTs from ordinal NFs. Standard immunohistological procedure was performed for Nnat, Tn-C and Ki-67 in 9 sporadic NFs, 15 diffuse NFs (NF1), 15 plexiform NFs (NF1) and 6 MPNSTs (NF1), as well as 5 normal skins. All of the MPNSTs showed positive staining for Nnat, Tn-C and Ki-67, in sharp contrast to completely negative staining in all sporadic or NF-1-derived NFs. The aberrant expression of Nnat and Tn-C was a useful marker for distinguishing MPNSTs from benign NFs.