This study investigated subjective, cardiovascular, and cellular immune system responses in 20 healthy young men during brief mental arithmetic stress compared with a video-watching control task. The role of endogenous opioids in mediating the immunological change to stress was examined by pre-task administration of the opiate antagonist naloxone. Immune changes were followed over a 1 hr post-task period. The results indicate significant physiological arousal and subjective distress as well as increases in NK cell cytotoxicity, numbers of circulating CD8 suppressor/cytotoxic T cells and NK lymphocytes following mental arithmetic but not the control task. Immune measures generally returned to baseline by 1 hr after the stress. Naloxone did not block the increase in NK cell activity or cell numbers following the stressor and had no effect on the other physiological or subjective measures. Thus, the results do not support endogenous opioids as a primary mechanism for immune changes to this type of acute stress. Naloxone did, however, increase NK cell cytotoxicity during the video task without effecting NK cell numbers, suggesting naloxone itself can increase per-cell NK cytotoxicity. Affective ratings for the week preceding testing were inversely related to the increase in NK cell numbers during mental arithmetic. If the increase in NK cell numbers under brief stress is part of an adaptive response to potential injury, then our data suggest that increases in general distress may impede normal immune system adaptation. Acute stress paradigms may be used as potential probes for investigations of individual differences in immune system responsivity.