Recently, it was demonstrated that intracerebroventricular (icv) injection of interleukin-1 (IL-1) stimulated circulating interleukin-6 (IL-6) to a greater degree than intravenous (iv) injection of IL-1. The goal of this study was to compare the efficacy of lipopolysaccharide (LPS), injected both icv and iv, on circulating concentrations of IL-1 and IL-6. Both iv and icv injection of LPS stimulated plasma levels of IL-1 to a similar degree. However, iv injection of LPS was significantly more efficacious than icv injection of LPS in elevating circulating IL-6. These results demonstrate that like iv injection of LPS, icv injection of LPS stimulates plasma levels of IL-1 and IL-6. Increases in circulating cytokines during infectious diseases which are limited to the central nervous system may serve to activate peripheral functions of an acute phase response.