Several murine tumor-cell lines were tested by isotope release assays for their susceptibility to lysis by either activated peritoneal macrophages (apMPh), macrophage-like (MPh-like) cell lines, or natural killer (NK) cells. The qualitative selectivity of tumor-cell lysis by these different effector cells was quite disparate. The rank order of target cell susceptibility to lysis by apMPh in 24 h assay was L5178Y greater than P815 approximately equal to RL male greater than YAC-1 approximately equal to MBL-2. This was seen regardless of whether peritoneal MPh (pMPh) were activated by LPS or poly I:C. Two MPh-like cell lines, PU-5R and FC-1, had a pattern of cytotoxic activity against these target cells that closely paralleled that associated with apMPh, although levels of reactivity differed quantitatively among the effector cells. In contrast, the MPh-like cell line RAW-264 expressed a qualitatively different pattern of target-cell selectivity, preferentially lysing MBL-2, which was relatively refractory to lysis by other MPh-like cell lines or apMPh in the 24 h cytolytic assay. When spontaneous or interferon (IFN)-augmented NK activity was measured against the same panel of target cells, the pattern of selectivity was qualitatively different from that observed for apMPh. The consistent rank order of susceptibility to lysis by NK cells was YAC-1 greater than RL male 1 greater than P815 approximately equal to L5178Y approximately equal to MBL-2. The characteristic patterns of target-cell selectivity for apMPh or NK cells were the same for all of the strains of mice tested. From the different selectivity patterns of apMPh and NK cells, it is concluded that lysis of target cells is not based solely on inherent sensitivity to cytolysis. Instead, selectivity of lysis is probably due to variations in expression of target-cell structures recognized by each type of effector cell, and/or in susceptibility to the lytic mechanism(s) of the various effector populations.