The ultraviolet radiation-induced fibrosarcoma 1591 is generally rejected by normal syngeneic mice, but occasionally the tumor succeeds in growing progressively. Analysis of these progressively growing tumors has regularly demonstrated the development of tumor variants that have acquired a heritable progressive growth potential. We have analyzed the phenotypic changes of these variants to determine which kind of selection pressure had occurred during the evolution of the variants, thus giving insight into the relative importance and hierarchy of the different immune defense mechanisms that may be operating in normal individuals as a defense against neoplastic cells. We discovered that all of the host-selected progressor variants had lost not only a strong T cell-recognized and tumor-specific antigen, but also their high sensitivity to cytotoxic macrophages. No selection for macrophage-resistance or loss of the tumor antigen was observed in 1591 tumors reisolated from idiotypically-suppressed mice or from other mice lacking tumor-specific T cell immunity. Analysis of other tumor variants selected in vitro showed that 1591 tumor cells have the potential to lose sensitivity to tumoricidal macrophages without losing the T cell-recognized tumor antigen. Thus the data suggest that T cells and macrophages act together to suppress the outgrowth of potentially malignant cells in vivo.