The metabolic and physical properties of tumor cells that are associated with their ability to resist or escape from immune attack have been investigated. The susceptibility of P815 murine mastocytoma cells to immune killing can be modulated. Culturing the cells with adriamycin or with hydrocortisone increases or decreases, respectively, the sensitivity of the cells to killing by antibody (Ab) plus complement (C); in addition, culturing the cells with mitomycin C or hydrocortisone increases or decreases, respectively, the sensitivity of the cells to killing by cytotoxic T lymphocytes (CTL). The susceptibility of the cells to Ab-C killing correlates with the ability of the cells to synthesize complex cellular lipids, but not DNA, RNA, protein, or carbohydrate. Further, tumor cells rendered sensitive to Ab-C killing by adriamycin are decreased in total lipid content and in their cholesterol/phospholipid mole ratio; hydrocortisone-treated resistant cells showed the opposite effects. The ability of tumor cells to resist CTL killing did not correlate with their total cellular lipid synthesis, but did correlate with the synthesis and composition of specific cellular phospholipids. In addition, tumor cells increased in sensitivity to Ab-C killing exhibited an increase in cell surface membrane fluidity, whereas cells increased in susceptibility to CTL attack showed an increase in their net negative cell surface charge density. These data show certain unique chemical and physical properties of tumor cells to be of fundamental importance for their ability to resist either humoral or cell-mediated immunologic attack; modulation of one or another of these cellular properties results in a change in the cells' susceptibility to immune killing by antibody plus C or by cytotoxic T lymphocytes.