We tested the hypothesis that heat shock protein (Hsp) induction and cell death are mutually exclusive responses to stress. Despite activation of heat shock transcription factor 1 at temperatures ranging from 40 to 46 degrees C, Hsp72 and Hsp27 were not induced above 42 degrees C. Moreover, cells underwent apoptosis at 44 degrees C and necrosis at 46 degrees C, with mitochondrial cytochrome c release at both temperatures. However, only apoptosis was associated with caspase activation. Treatment of cells with z-VAD-fmk prior to heat shock at 44 degrees C failed to restore Hsp induction despite inhibition of heat-induced apoptosis. Furthermore, accumulation of Hsps after incubation at 42 degrees C rendered the cells resistant to apoptosis. These results suggest that lack of Hsp induction is the cause rather than the consequence of cell death.