Five paired human cell lines consisting of either skin fibroblasts or tumor obtained from patients with osteogenic sarcoma were studied for their susceptibility to macrophage mediated cytotoxicity. In two of the matched pairs, the malignant cell lines were susceptible to the effects of cytotoxic macrophages, whereas normal targets were not. In two other pairs, both malignant and normal targets were resistant to the effects of cytotoxic macrophages. In the fifth pair, both targets were sensitive to the effects of the macrophages. Cell surface sialic acid content of the five matched pairs and several previously studied targets was determined. It was found to correlate with susceptibility to macrophage mediated cytotoxicity. The resistant normal cell lines contained approximately 50% less sialic acid than did the sensitive tumor cell lines. Furthermore, the three resistant tumor lines also had cell surface sialic acid content in the range of the normal resistant targets. Sensitive tumor cells with high cell surface sialic acid, after neuraminidase treatment, became resistant to the effects of cytotoxic macrophages and the effect of the neuraminidase treatment was blocked by addition of sialic acid to the incubation mixture. Thus, it appears that susceptibility to macrophage mediated cytotoxicity is associated with increased levels of sialic acid on the cell surface membranes.