Background. Surgical procedures suppress host antitumor defense mechanisms, which may increase the risk of metastatic tumor dissemination. We have evaluated the effects of the biologic response modifier polyadenylic-polyuridylic acid (PAPU) on natural cytotoxicity in patients with breast cancer undergoing operation. Methods. PAPU (150 mg) or placebo was given intravenously during the perioperative period(preoperative, days -1 and 0; postoperative, day 1, 3, 5, 7, and 14). The function (chromium release assay) and number (flow cytometry) of natural killer (NK) cells were measured before operation (days -2 and -1), on the day of operation (day 0), and after operation (day 1, 2, 4, 6, and 18). Results. Surgical procedures suppressed NK cell cytotoxicity in the placebo group on postoperative days1 (p<0.001), 4, 6, and 18 (p<0.05), wherea inhibition on postoperative day 2 failed to reach significance. PAPU abolished this immunosuppression after operation. The NK cell activity was elevated when compared with the control group; it was significant (p<0.05) on postoperative days 1, 2, 4, 6, and 18. Surgical procedures also reduced circulating NK cell numbers during the first postoperative week in the placebo group; the decrease was statistically significant on day 4. The decrease in NK cell numbers in the PAPU group was insignificant. Conclusions. PAPU prevented the decrease in the circulating number and cytotoxic activity of NK cellsthat occurred after operation and enhanced NK cell cytotoxicity. This may have important implications for patients with cancer undergoing major operation.