The effects of general anesthesia on the levels of baseline and inducible splenic natural killer (NK) activity of mice were examined. General anesthesia significantly inhibited the induction of NK activity by Poly I:C, while having no effect on baseline NK. Since this effect was reproduced using three different anesthetics (Avertin, ether, and Ketamine/Xylazan), the inhibition of inducible NK activity is probably due to the state of general anesthesia, rather than to the pharmacological properties of the anesthetics. Inhibition of the Poly I:C mediated induction of NK was observed for at least 4 days after anesthesia. In contrast to anesthesia alone, anesthesia with surgery significantly decreased baseline NK activity. However, the addition of surgery to anesthesia did not significantly alter the level of inhibition of NK stimulation by Poly I:C compared to anesthesia treatment alone. Experiments assessing the NK modulatory effects of surgery alone were not performed. Interestingly, neither anesthesia alone nor anesthesia with surgery were able to significantly decrease splenic NK activity that had been induced with Poly I:C prior to anesthesia. In view of the important role of NK cells in the innate immune defenses, the possible clinical applications of these results are discussed.