In this study we show that the opioid peptide beta-endorphin exerts a tonic inhibitory effect on the proliferative response of splenocytes to the polyclonal mitogen phytohemoagglutinin throughout two separate sites of action: one central and one peripheral. The intracerebroventricular administration of beta-endorphin, in fact, induces a significant inhibition of splenocyte proliferation. In contrast, both the intracerebroventricular and the peripheral administration of anti-beta-endorphin gamma globulins induce a significant increase in proliferation. Moreover, an increase of splenocyte proliferation was observed also after the intravenous administration of gamma globulins and intraperitoneal naloxone, and this effect was still present in hypophysectomized rats. The data reported suggest that beta-endorphin exerts a tonic inhibitory effect on proliferation, acting centrally, and peripherally throughout a paracrine/autocrine mechanism. FAGS experiments show that the effect observed is not the consequence of an alteration of lymphocyte trafficking induced by the opioid.