From approximately 7 weeks gestational age in developing human peripheral nerve, as in adult nerve, S-100 protein was found to be expressed solely and uniformly by Schwann cells associated with axons. In embryos younger than 7 weeks S-100 was much less constant and many cells did not show clear staining. The trigger for the initial appearance of the protein at around this age remains unclear although a relationship of S-100 expression in Schwann cells to close axonal contact is suggested. The value of S-100 protein in distinguishing Schwann cells from perineurial cells in normal nerves and nerve sheath tumours remains unclear.