The present study compared the nociceptive responses of male and female mice exposed to a predator, an ecologically relevant threatening stimulus. After 15 min of exposure to the presence of an experienced predatory cat, mice displayed a naloxone (1.0 mg/kg)-sensitive opioid mediated analgesic response, while after a brief 30-s exposure to the cat mice displayed a lower amplitude, relatively brief, non-opioid analgesia that was insensitive to naloxone and blocked by the serotonin-1A (5-HT1A) agonist, 8-hydroxy-2-(di-n-propylamino)tetralin. Male mice displayed a significantly greater opioid mediated predator-induced analgesia than females, whereas female mice showed a significantly greater non-opioid, 5-HT1A sensitive, analgesia than males. These results indicate that there are significant sex differences in both the opioid and non-opioid analgesic responses arising from exposure to a natural aversive stimulus.