It is well established that serum plays an important role in cell proliferation and differentiation. In this study, we have identified a serum factor that induces rapid neurite retraction of morphologically differentiated NG108-15 cells, cultured in serum-free medium containing 1 mM-dibutyryl cyclic AMP. The serum fraction of Mr greater than 30 x 10(3) induces neurite retraction in a manner identical to that of the whole serum. The neurite retraction activity in serum appears to be acid- and heat-stable. The molecular weight of the serum neurite retraction factor (NRF) has been demonstrated to be approximately 70 x 10(3) by gel permeation on LKB-Ultrogel AcA-44. The neurite retraction activity is dose-dependent, and the time required for half-maximal activity (t1/2) is 1.8 min. NRF is present in sera of various species studied, including human, cattle, sheep, rabbit and horse, but not in tissue extracts of kidney, heart, lung skeletal muscle, and brain of the rat. However, rat spleen and liver homogenates, at a protein content of 1 mg ml-1, caused slight neurite retraction. It is noteworthy that NRF is not detectable in cerebral spinal fluid. Our data on the properties of serum NRF indicate that it differs from all of the well-established growth factors, namely, NGF, EGF, PDGF, FGF, NSILA, ECGF and TGF. Further studies on purified NRF will delineate the biological role(s) of this serum factor in the process of maturation and differentiation of developing neurones.