The natural killer (NK) cell system of mice in the peritoneal cavity is of very low to undetectable activity, and testing peritoneal NK cells is a useful model to study the influence of activating substances upon local injection. Injection of indomethacin at doses of 100-400 micrograms/mouse caused a marked activation of NK cell activity which was maximal at 3 days and lasted for a total of 6 days. A similar albeit less marked effect was observed with other cyclooxygenase inhibitors such as aspirin. Prostaglandin E2 reversed the activation of NK cells induced by injection of indomethacin. The cellular count of the peritoneal population was 2-fold elevated after indomethacin injection but the percentage of macrophages in the washed-out cell population was decreased from 60%(controls) to around 20%. The NK cell nature of the effector cells activated by indomethacin was substantiated by the finding that previous injection of anti-asialo GM1 antibody prevented activation. Interferon could not be detected in the peritoneal wash fluid after injection of indomethacin, suggesting interferon-independent activation. However, the possibility of small interferon quantities being locally produced could not be excluded. In further experiments we found after intraperitoneal injection of indomethacin not only cells that killed YAC-1 targets in a 4-hour assay but also killer cells that were insensitive to anti-asialo GM1 and killed P815 cells in an 18-hour assay. We assumed that these were macrophages and have done further experiments with in vitro grown bone-marrow-derived macrophages. These could be activated for killing of P815 targets by the addition of indomethacin, but (to a lesser degree) also for killing of YAC-1 lymphoma cells.