Thiamine deficiency results in selective neuronal damage. A number of mechanisms have been proposed to account for brain damage associated with thiamine deficiency and to account for the focal nature of the loss of neurons. One proposed mechanism is programmed cell death. We found efficient induction of apoptosis in human neuroblastoma cells when the cells were deprived of thiamine. Although extensive mitochondrial damage was seen, the release of cytochrome c was not the triggering mechanism for thiamine deficiency-induced apoptosis. Instead, the activity of the cJun amino terminal kinase Jnk1 was lost, and this loss correlated temporally with induction of apoptosis. The loss was specific for Jnk1; Jnk2/3 activity remained unchanged. Loss of Jnk1 activity was not found in lymphoblasts, a cell type that did not undergo apoptosis when deprived of thiamine. These findings suggest that thiamine deficiency results in a cellular stress that brings about the loss of Jnk1 activity and the loss of its function of protecting cells from programmed cell death. We postulate that focal sensitivity to thiamine deficiency results, in part, from specific neuronal cell types being susceptible to the inactivation of Jnk1 in response to depletion of cellular thiamine.