It has been well documented that interleukin-1β (IL-1β) is a major mediator for recruiting the hypothalamo-pituitary-adrenal (HPA) axis following infectious disease. The recent localization of IL-1β receptors in neurons of the hippocampus provides further support for the role of IL-1β as a neurotransmitter/neuromodulator in the central nervous system. In this study, we investigated whether an acute intrahippocampal injection of IL-1β is able to rapidly stimulate HPA activity. Seven days after bilateral implantation of a guide cannula into the hippocampus, human IL-1β (10 ng/0.5 µl/side) was injected to freely moving male rats. Following this, animals were sacrificed at times 20, 45 and 90 min postinjection and a kinetic analysis of hIL-1β action on plasma ACTH and corticosterone (CORT) concentrations and nuclear processing of the anterior pituitary (AP) proopiomelanocortin (POMC) was conducted. Intrahippocampal administration of hIL-1β significantly increased both plasma ACTH and CORT concentrations at 45 and 90 min postinjection. This increase in ACTH concentration paralleled a rise in AP POMC gene transcription. Moreover, the increase in AP POMC primary transcript was followed by an increase in AP POMC intermediate processing RNA. However, at these times, no significant hIL-1β effect on the level of AP nuclear POMC mRNA was observed. Almost identical results were obtained after intraperitoneal injection of hIL-1β. In conclusion, our data demonstrates that the hippocampal IL-1β/IL-1β receptor is directly and rapidly implicated in HPA activation, in the same manner as that observed after intraperitoneal administration of hIL-1β. These results show that IL-1 action in the hippocampus could be of immunoneuroendocrine significance for the HPA axis activation during inflammatory states.