We investigated consequences of ischemia/reperfusion stress on in vitro models with various types of mammalian cells undergoing hypoxia/reoxygenation. Cultured rat cardiomyocytes (H9c2 line), murine fibroblasts, human vascular endothelium and human kidney epithelium (293 line) were here used for the experiments with prolonged hypoxia (N2 atmosphere, <1% O2, for 18-20 h) followed by reoxygenation under normoxic conditions (21% O2). We found that, independently on cell type, some percentage (8-35%) of the reoxygenated cells dies via mitochondria-dependent apoptosis. Besides, macroautophagic events were clearly observed in all the reoxygenated cells what was manifested in formation of autophagosomes entrapping stress-damaged mitochondria and subsequent formation of large autolysosomes digesting the entrapped mitochondria. Some fraction (5-20%) of those cells underwent autophagic death (i.e. lethal autolysis) afterwards, whereas the other cells survived and even became more resistant to the repeated hypoxia/reoxygenation stress. When we performed stressful preconditioning by means of mild hyperthermia (43 C for 60 min) or shorter (8-10 h) hypoxia, such pretreated cells acquired the enhanced resistance to subsequent (severe) hypoxia/reoxygenation stress: the percentage of apoptotic and autophagic death considerably decreased, although the post-stress macroautophagic processes were not impaired in the preconditioned cells. Furthermore, upon post-hypoxic reoxygenation in the preconditioned (resistant) cells, uptake of mitochondria by autophagosomes began earlier and more intensely as compared with non-preconditioned control; this discrepancy correlated with the decrease in apoptosis and improved survival of the preconditioned cells. In the case of pretreatment with rapamycin, a known inhibitor of macroautophagy, the reoxygenated cells did not exhibit macroautophagic events but, instead, massively died via apoptosis and necrosis. Moreover, rapamycin prevented the acquisition of resistance to the hypoxia/reoxygenation stress after the preconditioning. We suggest that macroautophagy is the characteristic cellular reaction to hypoxia/reoxygenation; this reaction is aimed at compartmentalization of stress-damaged mitochondria into autophagosome followed by their digestion by autolysosomes. Such responses allow some post-hypoxic cells to escape apoptosis resulting from the mitochondrial damage. In some cases, macroautophagy appears to kill the reoxygenated cells if their mitochondrial damage is too severe. According to our observations, the stressful preconditioning may switch the post-hypoxic macroautophagy from its lethal mechanism to the adaptive one. It seems likely that the stress-inducible heat shock proteins are involved in this cytoprotective switching.