Serum samples from patients with peripheral von Recklinghausen's disease were studied by competition radioreceptor assays and radioimmunoassays for biologically active 2.5S subunit of nerve growth factor (NGF). These specimens were fractionated at low pH to partially purify a 2.5S NGF-like activity that specifically competes for the binding of radioisotope-labeled 2.5S NGF to its receptor on human melanoma cells. In seven patients with peripheral neurofibromatosis, statistically significant elevations of this 2.5S NGF competing activity were found: approximately 85% of the patients tested had competing activities outside the 95% confidence limits of the normal population. No elevations of competing activity were observed when these serum fractions were examined by a specific radioimmunoassay for purified 2.5S NGF. These conflicting observations may suggest the existence of two molecular species demonstrating NGF-like activity: one sharing antigenic determinants with mouse 2.5S NGF and the other antigenically unrelated. We identified an NGF binding activity of high molecular weight in human serum. This activity is not elevated in the serum of patients with peripheral neurofibromatosis.