Macrophage-rich adherent peritoneal cells from mice sensitized by two i.p. injections of allogeneic cells at days -- 12 and --2, were found non-specifically cytotoxic against (a) tumoral target cells, as evaluated by the chromium release test, and (b) normal target cells, as evaluated by a functional test based on the insulin secretion response to glucose stimulation of isolated pancreatic islet cells. This non-specific cytotoxicity was identical to that of macrophages "activated" by an in vitro incubation with supernatants of MLC between allograft donor and recipient as reported elsewhere. Moreover this cytotoxicity was not abolished by anti-theta serum treatment of adherent peritoneal cells before contact with target cells. It is concluded that an in vivo macrophage activation was obtained in our experiment. Using this same model, we found that the survival time of skin grafts from male C57BL/6 to female C57BL/6 mice was shortened if the graft was performed at the time when the recipient macrophages were found non-specifically cytotoxic (two days after the second allogeneic cell injection). The role of macrophage cytotoxicity in this accelerated allograft rejection is suggested by (a) the lack of any detectable cross-histocompatibility antigens between the immunizing cells and the skin graft, and (b) the absence of any alteration of the graft survival if the second immunizing injection two days prior to grafting is omitted (in that case only lymphocytes are found specifically cytotoxic against the strain of injected cells, while the non-specific cytotoxicity of macrophages is lacking).