The effect of lipopolysaccharide (LPS) on murine unstimulated and prestimulated natural killer (NK) cells and its ability to serve as an unconditioned stimulus was investigated. LPS injection induced a statistically significant increase in NK cell activity when compared with saline-treated control groups. To demonstrate the existence of communication between the peripheral immune system and the central nervous system (CNS), we used a single-trial conditioning paradigm in which camphor served as the conditioned stimulus (CS) and LPS as the unconditioned stimulus (US). Once a CS/US association is made, exposure of animals to the CS alone results in the conditioned response (i.e., increase in NK cell activity). Using 50 μg of LPS as the US produced a low but significant increase in NK cell activity when compared to control groups. However, 10 μg of LPS did not show a significant increase in NK cell activity. We also observed that interleukin-1α (IL-1α) injected intracistemally can serve as a US to condition a central neuroendocrine pathway. Because the dose of IL-1α employed was too small to raise NK cell activity in the spleen, the NK cells themselves were formally not subjected to conditioning. These observations suggest that LPS and IL-1α conditions the brain and that NK cell activity can be used as an indicator system to detect neuroendocrine signals arising from the activated pathway(s).