We have used the pairing of camphor odor conditioned stimulus (CS) and injection of poly I:C unconditioned stimulus (US) in a short 3 day single trial conditioning paradigm. Conditioning was done by exposing mice to the CS/US combination on day 0 and reexposing the conditioned animals to the CS on day 2. This results in a conditioned augmentation of the natural killer (NK) cell response. Indomethacin treatment and/or handling stress induced by simply measuring rectal temperature was found to dramatically alter the direction of the conditioned NK cell response. Conditioning of indomethacin treated mice produced a conditioned suppression of the NK cell response mimicking a conditioned tolerance response. If handling stress was superimposed on day 2 the conditioned suppression response was replaced by a conditioned augmentation of the NK cell response. Even with one trial conditioning, drugs and handling stress can serve as additional cues to alter the direction of the conditioned response. The studies also show that the conditioning of the fever response is independent of conditioning of the NK cell response.