The specific mechanism of interaction between the central nervous system and immune system was examined using conditioned augmentation of natural killer (NK) cell activity. This study focused on the role of interferon-β (IFN-β) as the unconditioned stimulus (US). IFN-β was found to be the signal responsible for the bidirectional communication which links the central nervous system with the immune system. This was substantiated by injection of small quantities of IFN-β directly into the cisterna magna, which activated the effector pathway from the central nervous system to the immune system. More importantly, we found that when the conditioned stimulus (CS) was paired with an injection of IFN-β into the cisterna magna, the conditioned animals were able to raise their natural killer cell activity in response to subsequent exposure to the conditioned stimulus. These studies show the unconditioned response must be the response of the central nervous system (CNS) to the unconditioned stimulus and not the direct effect of the substance injected into the periphery. © 1993.