TNF-alpha elicits various responses including apoptosis, proliferation, and differentiation according to cell type. In neuronal PC12 cells, TNF-alpha induces moderate apoptosis while lipopolysarccaharide or trophic factor deprivation can potentiate apoptosis that is induced by TNF-alpha. TNF-alpha initiates various signal transduction pathways leading to the activation of the caspase family, NF-subk;B, Jun N-terminal kinase, and p38 MAPK via the death domain that contains the TNF-alpha receptor. Inhibition of translation using cycloheximide greatly enhanced the apoptotic effect of TNF-alpha. This implies that the induction of anti-apoptotic genes for survival by TNF-alpha may be able to protect PC12 cells from apoptosis. Accordingly, Bcl-2, an anti-apoptotic Bcl-2 family member, was highly expressed in response to TNF-alpha. In this study, we examined the anti-apoptotic role of p38 MAPK that is activated by TNF-alpha in neuronal PC12 cells. The phosphorylation of p38 MAPK in response to TNF-alpha slowly increased and lasted several hours in the PC12 cell and DRG neuron. This prolonged and slow phosphorylation of p38 MAPK was distinct from other non-neuronal cells. The specific inhibitor of p38 MAPK, SB202190, significantly enhanced the apoptosis that was induced by TNF-alpha in PC12 cells. This indicates that the activation of p38 MAPK could protect PC12 cells from apoptosis since there is no known role of p38 MAPK in response to TNF-alpha in neuron. This discovery could be evidence for the neuroprotective role of the p38 MAPK.