The suppression of natural killer (NK) cell cytotoxicity by footshock stress can be attenuated by opioid antagonists, implicating endogenous opioids in its mediation. A stress paradigm that induces NK suppression that is not blocked by the opioid antagonist naltrexone is reported. This stress paradigm is also shown to cause analgesia and elevated plasma corticosterone levels that are not attenuated by naltrexone. In the first experiment, a significant suppression of NK cell cytotoxicity after forced swimming was demonstrated in Fischer 344 rats treated with either saline or naltrexone, compared with nonstressed controls. Significantly higher corticosterone levels were evident in both stressed groups. In the second experiment, the same stress paradigm was shown to cause significant analgesia in the tail-flick test, whereas no differences were seen between groups pretreated with saline and naltrexone. It is concluded that opioids need not always be involved in the suppression of NK cell cytotoxicity by stress.