The effect of the intracerebroventricular (icv) and intravenous (iv) injection of nerve growth factor (NGF) on peripheral immunity was studied in the rat. Icv administration of NGF (5, 25, 50, 250 and 500 ng/rat) significantly enhanced phytohemagglutinin (PHA)-induced splenocyte proliferation 30 min after treatment. Icv pretreatment with an anti-NGF antibody completely prevented the effect, while iv injection of anti-NGF antibody did not block the effect of icv NGF. On the contrary, NGF at doses of 0.5, 2.5, 5, 25 and 50 ng/rat decreased splenocyte natural killer (NK) activity. When injected iv, NGF enhanced splenocyte proliferation only at doses of 50 and 500 ng/rat, while it did not affect NK activity. These effects on immunity do not appear mediated by activation of the hypothalamus-pituitary-adrenal axis, since NGF did not modify plasma corticosterone concentrations at the doses used. These results indicate that NGF participates in the complex network of neuroimmune interactions.