The efficacy of varied diterpene ester type tumor promoters in suppressing the acquisition as well as the manifestation of cytolytic activity by macrophages was investigated. These mechanisms, believed to be basic to natural antitumor resistance, were markedly suppressed not only by the phorbol ester, TPA, but also by several other tumor promoters of the polyfunctional diterpene ester type covering tigliane, ingenane, and daphnane derivatives. The promoters were particularly effective in preventing the lymphokine-induced enhancement of natural cytolytic activity in resting macrophages. Moreover, the same promoters suppressed the manifestation of cytotoxicity by previously activated macrophages. Their influence on the effector phase was less pronounced than on the activation phase. In sharp contrast, typical solitary carcinogens of the polycyclic aromatic hydrocarbon type exerted little or no activity in the macrophage test systems. Since TPA had already been shown to suppress the natural killer activity in vitro and to abrogate host tumor resistance in vivo, the present findings lend further support to the interpretation that tumor promoters, apart from directly stimulating the outgrowth of transformed cells, may function via interference with natural antitumor effector systems.