We tested the hypothesis that central angiotensin II (Ang II) administration would activate splenic sympathetic nerve discharge (SND) which in turn would alter splenic cytokine gene expression. Experiments were completed in sinoaortic-denervated, urethane-chloralose anesthetized, splenic nerve-intact and splenic nerve-denervated, Sprague-Dawley rats. Splenic cytokine gene expression was determined using genearray and real-time RT-PCR analysis. Splenic SND was significantly increased after intracerebroventricular (icv) administration of Ang II (150 ng/kg, 10 µl), but not artificial cerebrospinal fluid (aCSF). Splenic mRNA expression of IL-1, IL-6, IL-2, and IL-16 genes was increased in Ang II-treated splenic-intact rats compared with aCSF-treated splenic-intact rats. Splenic IL-1, IL-2, and IL-6 gene expression responses to Ang II were significantly reduced in splenic-denervated compared with splenic-intact rats. Splenic gene expression responses did not differ significantly in Ang II-treated splenic-denervated and aCSF-treated splenic-intact rats. Splenic blood flow responses to icv Ang II administration did not differ between splenic-intact and splenic-denervated rats. These results provide experimental support for the hypothesis that Ang II modulates the immune system through activation of splenic SND, suggesting a novel relationship between Ang II, efferent sympathetic nerve outflow, and splenic cytokine gene expression.