Over-expression of the major heat-shock protein hsp70 in WEHI-S tumor cells renders them resistant to the cytotoxic effects of tumor necrosis factor (TNF). To study the significance of this resistance in vivo, the tumorigenic potential of WEHI-S cells transfected with human hsp70 in sense and anti-sense orientation was investigated in athymic and in normal syngenic mice. A striking correlation was observed between the level of hsp70 expression and tumorigenicity in athymic mice. Hsp70 expression rendered WEHI cells tumorigenic also in normal mice, but higher numbers of cells were required for tumor formation than in athymic mice. Over-expression of hsp70 in WEHI-S cells did not enhance their anchorage-dependent growth in vitro or their ability to form colonies in soft agar. The hsp70-transfected cells exhibited greatly increased resistance against killing by murine natural cytotoxic cells and macrophages in vitro. A similar tumorigenic phenotype could also be induced independently of hsp70 by prolonged culture of WEHI-S cells with TNF. These results suggest that over-expression of hsp70 increases the tumorigenic potential of WEHI-S cells in mice, by allowing these cells to escape from the early TNF-mediated anti-tumor immune surveillance.