The present experiments were designed to elucidate the effect of direct orbitofrontal cortical administration of interleukin-1beta (IL-1beta) on the homeostatic regulation. Short- and long-term food intakes (FI), water intakes and body temperature (BT) were measured before and after a bilateral microinjection of IL-1beta (with or without paracetamol /P/ pretreatment) into the orbitofrontal cortex (OBF) of Wistar rats, and the effects were compared with those found in vehicle-treated and i.p. injected IL-1beta, IL-1beta+P or control animals. In addition, blood glucose levels (BGLs), along a glucose tolerance test, and plasma concentrations of insulin, leptin, cholesterol, triglycerides and urate were determined in cytokine treated and control rats. Short-term FI was suppressed after orbitofrontal cortical or peripheral application of IL-1beta. In the long-term FI, however, there was no significant difference among the groups. Cytokine microinjection into the OBF, similar to the i.p. administration, was also followed by a significant increase in BT. Pretreatment with P failed to influence the anorexigenic and hyperthermic effects of the centrally administered IL-1beta. The sugar load led to a diabetes-like prolonged elevation of BGL in the IL-1beta treated animals. Following cytokine administration, plasma levels of insulin and that of triglycerides were found decreased, whereas that of uric acid increased. The present findings confirm that the OBF is one of the neural routes through which IL-1beta exerts modulatory effect on the central homeostatic regulation.