An elevation of natural killer (NK) cell activity was conditioned by the association of a camphor odor conditioning stimulus (CS) with an injection of 20 μg poly-inosinic:poly-cytidylic acid (poly I:C), the unconditioned stimulus (US). Poly I:C elicits the production and secretion of interferon (IFN), which induces an increase in NK cell activity. Reexposure to the CS occurred on Days 3 and 5 after the association trial on Day 0. Immediately following the CS exposure on Day 5, 1 μg poly I:C was administered to all animals. This procedure resulted in an increased NK cell activity in the conditioned (CND), but not the nonconditioned (NC), mice. In this study we have shown that the expression of the conditioned response was blocked by an injection of naltrexone (NTX) at 10 mg/kg ip when given immediately prior to the two test CS odor exposures. Peripheral treatment (ip) with a quaternary form of naltrexone (QNTX), which is a less potent opiate antagonist, at the same dose and at the same time relative to the CS odor reexposure did not block the conditioned response. The formation of the conditioned association did not appear to be disrupted by NTX at the 10 mg/kg dose when given immediately prior to the trial odor exposure on Day 0. No modulation of NK cell activity was observed in any of the control groups treated with naltrexone or the quaternary analog. Because of the inability of the QNTX to block the conditioned response, we hypothesize that the opiate receptors involved in the conditioned response and blocked by NTX were within the central nervous system (CNS). Whether this response is peripherally or centrally mediated, we have shown that opiate receptors represent part of the mechanism which mediates the conditioned augmentation of NK cell activity. © 1989.