Normal immune homeostasis is regulated partly by a small population of CD4+T cells that react to autologous major histocompatibility complex class‐II molecules on self‐cells. Decreased autoreactive T‐cell responses are associated with cancer. Tumour growth causes syngeneic macrophages (Mø) to suppress autoreactive T‐cell proliferation by decreasing Mø class‐II expression and increasing Mø production of the suppressor molecule prostaglandin E2(PGE2). Because interferon‐γ (IFN‐γ) is a potentMøactivation molecule which regulates both Mø PGE2and class‐II expression, the effects of IFN‐γ on tumour‐induced suppression of autoreactive T‐cell proliferation were investigated. Exogenous IFN‐γ increased normal host (NH) CD4+autoreactive T‐cell proliferation stimulated by syngeneic NHMø but decreased proliferation stimulated by tumour‐bearing host (TBH) Mø. Antibody (Ab) neutralization of endogenous IFN‐γ activity reduced TBH Mø‐mediated suppression. Kinetic studies showed that endogenous IFN‐γ suppressor activity was not exclusive during T‐cell activation. Indomelhacin treatment blocked IFN‐γ‐induced suppression in TBH Mø‐T cell cultures. TBH Mø‐T cell cultures contained significantly more PGE2than those containing NH Mø. Exogenous IFN‐γ increased early PGE2production in TBH Mø cultures but decreased production in NHMø cultures. The Ab‐mediated neutralization of endogenous transforming growth factor‐β or tumour necrosis factor‐x reduced TBH Mμ‐mediated suppression and blocked IFN‐γ‐induced suppression. Short‐term treatment of Mμ with IFN‐γ before their addition to T cells caused TBH Mμ to stimulate T‐cell proliferation, which suggests that early suppressor molecule production by TBHMø inhibits synthesis or activity of IFN‐γ‐induced stimulatory monokines. These results show that tumour growth causes Mø to suppress autoreactive T‐cell responses by allowing I