The expression of pro-inflammatory cytokines increases in the hypothalamus of rats with heart failure (HF). The pathophysiological significance of this observation is unknown. We hypothesized that hypothalamic pro-inflammatory cytokines upregulate the activity of central neural systems that contribute to increased sympathetic nerve activity in HF, specifically, the brain renin-angiotensin system (RAS) and the hypothalamic-pituitary-adrenal (HPA) axis. Rats with HF induced by coronary ligation and sham-operated controls (SHAM) were treated for 4 weeks with a continuous intracerebroventricular (ICV) infusion of the cytokine synthesis inhibitor pentoxifylline (PTX, 10 µg/hr) or artificial cerebrospinal fluid (VEH). In VEH-treated HF rats, compared with VEH-treated SHAM rats, the hypothalamic expression of pro-inflammatory cytokines was increased, along with key components of the brain RAS (renin, angiotensin converting enzyme, angiotensin type-1 receptor) and corticotropin releasing hormone, the central indicator of HPA axis activation, in the paraventricular nucleus (PVN) of hypothalamus. The expression of other inflammatory/excitatory mediators (superoxide, prostaglandin E₂) was also increased, along with evidence of chronic neuronal excitation in PVN. VEH-treated HF rats had higher plasma levels of norepinephrine, angiotensin II, interleukin-1 beta, and adrenocorticotropic hormone, increased left ventricular end-diastolic pressure and increased wet lung/body weight ratio. With the exception of plasma interleukin-1 beta, an indicator of peripheral pro-inflammatory cytokine activity, all measures of neurohumoral excitation were significantly lower in HF rats treated with ICV PTX. These findings suggest that the increase in brain pro-inflammatory cytokines observed in rats with ischemia-induced heart failure is functionally significant, contributing to neurohumoral excitation by activating brain RAS and the HPA axis.