Pro-inflammatory cytokines interleukin (IL)-6 and IL-1 beta can act in the brain (centrally) to cause fever. Sickness behaviors which accompany fever also appear to involve the central action of IL-1 beta. We injected species-homologous rat IL-6 and IL-1 beta directly into the brains of conscious rats to examine the effect of these cytokines on fever, and two behaviors affected by sickness, voluntary wheel-running and food intake. Male Sprague-Dawley rats selected for their predisposition to spontaneously run on running wheels were used in the experiment. Each rat was anaesthetized and had a temperature-sensitive radiotransmitter implanted intra-abdominally, and a 23-gauge stainless steel guide cannula inserted stereotaxically over the lateral cerebral ventricle. Rats were randomly assigned to receive intracerebroventricular injections of three doses of either IL-1 beta or IL-6 (100 ng, 1 ng or 0.1 ng IL-1 beta and 200 ng, 20 ng or 2 ng IL-6), or one of three different combinations of IL-1 beta and IL-6. Rats receiving either IL-1 beta or IL-6 showed a dose-dependent increase in body temperature and decrease in wheel-running (ANOVA, p<0.0001). Only rats receiving the highest dose of IL-1 beta significantly decreased food intake and body mass compared to rats receiving vehicle (ANOVA, p<0.001). Doses of IL-1 beta and IL-6 which, when injected on their own were non-pyrogenic and did not affect food intake and body mass, induced fever and anorexia when they were co-injected centrally. These results show that species-homologous rat IL-6 and IL-1 beta can act directly within the brain to decrease voluntary activity and suggest they also can act synergistically to induce anorexia and fever.