Low levels of H2O2 can induce cellular resistance to subsequent higher levels of H2O2. By using human U937 leukemia cells, it was previously shown that such an adaptive response can be induced without increasing the cellular capacity to degrade H2O2, thus conferring on the cells a cross-resistance to other stimuli such as serum withdrawal and C2-ceramide. In this study, it was found that stress-activated protein kinase/c-Jun N-terminal kinase (SAPK/JNK) acts as a common mediator of the cell death induced by high H2O2 concentrations, serum withdrawal and C2-ceramide. Although SAPK/JNK activation by H2O2 was mediated by two upstream mitogen-activated protein kinase (MAPK) kinases MKK4 and MKK7, only MKK7 played such a role in serum withdrawal and C2-ceramide. Interestingly, all these lethal stimuli failed to activate SAPK/JNK and its upstream kinases in the cells that were pretreated with low adaptive concentrations of H2O2. By contrast, the phosphorylation levels of extracellular signal-regulated kinase and p38 MAPK were not significantly influenced by this H2O2 pretreatment. Inducing the SAPK/JNK-suppressing effect of H2O2 required a time lag, which correlated with the time lag required for the induction of the adaptive response. Overall, the results suggest that H2O2 adaptation confers on cells a resistance to multiple stimuli by specifically blocking their ability to activate the SAPK/JNK pathways.