We have demonstrated that immunotherapy of young (6-10 weeks old), and aged, (greater than 24 months old), tumor bearing mice with biological response modifiers enhanced survival and inhibited tumor growth, while treatment of aged mice had little or no effect. We hypothesized that the antitumor activity in young mice was principally mediated by activated macrophages (M phi) and predicted that the change in aged mice was caused by an intrinsic M phi defect which develops with advancing age. To directly test our hypothesis, we examined the antitumor activity of resident peritoneal M phi, purified and activated in vitro with IFN gamma plus LPS. Paralleling the results seen in vivo, M phi from aged mice exhibited reduced antitumor activity in comparison with M phi from younger mice. Moreover, there was reduced capacity of in vitro activated M phi from aged mice to produce TNF, IL-1 and nitric oxide, which are critical monokines and effector molecules that have been established to either directly inhibit tumor growth or cause tumor cell destruction. These studies establish that peritoneal M phi from aged mice have an intrinsic defect which prevents them from fully expressing their antitumor potential.