OBJECTIVE:: The nerve growth factor (NGF) is the main neurotrophin, which besides being an important growth factor for nerves and plays an important role as a mediator of inflammation. Nerve growth factor has been shown to increase in relation to stress stimuli and in allergic diseases in humans and after physical exercise in animal models. This study aims at evaluating NGF serum levels in top athletes, a population sample in which allergic and neuro-immune diseases are reported with a significantly increased prevalence. DESIGN:: Observational, cross-sectional, multicenter study. SETTING:: Institutional, tertiary care. PARTICIPANTS:: Ninety-six Italian pre-Olympic athletes (44 allergic and 52 nonallergic) and 49 matched controls selected within the Italian National Olympic delegation (n = 435). INDEPENDENT VARIABLES:: Nerve growth factor serum levels determined through an enzyme-linked immunosorbent assay. MAIN OUTCOME MEASURES:: Parametric or nonparametric tests were used for comparing NGF serum levels among different study groups depending on value distributions. RESULTS:: Nerve growth factor serum levels were significantly higher in athletes than in controls independently from the presence of allergy. Nerve growth factor mean values were 368.3 ± 776.3 pg/mL in the sample of athletes and 174.1 ± 483.7 pg/mL in the control group (P < 0.001). CONCLUSIONS:: This is the first study showing that intense and prolonged physical exercise is associated with an increase of NGF serum levels in athletes. Whether the increased NGF production might be linked to the prevalent Th2 response observed in allergic diseases and after physical exercise and whether might be related to the patophysiology of neuro-immune disorders as the amyotrophic lateral sclerosis, reported with a higher prevalence in athletes, should deserve further investigations.