Surgical stress and general anesthesia can suppress immune function and thus may increase postsurgical infections and tumor metastasis. We previously reported that two narcotics commonly used in high-dose opiate anesthesia (fentanyl and sufentanil) suppress natural killer (NK) cell activity in rats. Such doses of narcotics also cause respiratory depression accompanied by hypoxia, hypercarbia, and acidosis, which might account for the observed narcotic-induced NK suppression. In the present study, we compared the effects of fentanyl on NK activity in ventilated and non-ventilated rats. Fentanyl significantly suppressed NK cell activity to the same magnitude in the two groups, although the groups significantly differed in CO2 and O2 levels. The fact that high-dose fentanyl-induced NK suppression can be demonstrated in ventilated rats accentuates the relevance of these findings to clinical studies showing NK suppression in the immediate postoperative period. Such immunosuppression could be a risk factor for patients undergoing surgery, especially in cancer-related operations.