Suppression of natural killer (NK) cell activity in the postoperative period has been reported in several clinical studies. Endogenous opioids and cerebral injection of morphine have been shown to suppress NK cell activity. Since high-dose opiates are commonly used in anesthetic practice, we sought to determine the effects of three narcotic agents on NK cell activity. Male rats were injected subcutaneously with morphine (30 mg/kg), fentanyl (0.3 mg/kg), or sufentanil (0.06 mg/kg). Three, 12, or 24 h later the cytotoxic activity of splenic NK cells was measured in a 4-h chromium-51 release assay using radiolabeled target cells. All three drugs significantly suppressed NK cytotoxicity at 3 h after administration; this effect was blocked by an opiate antagonist, naltrexone. Fentanyl and sufentanil also caused a significant suppression 12 h after drug administration. By 24 h NK activity of all groups returned to normal values. Interferon is known to augment NK cell activity. Therefore, in another experiment rats were given an interferon inducer, polyinosinic:polycytidylic acid (poly I:C), to determine if it would alter the effects of these narcotics on splenic NK activity. Poly I:C treatment increased NK cytotoxicity to above baseline; fentanyl in these animals reduced NK activity and brought it back to control levels. These findings suggest that clinically used high-dose narcotic anesthesia can suppress NK cytotoxic activity and that pretreatment with interferon can attenuate this suppression.