In order to elucidate underlying mechanism of cell death pathways in neuronal cells in humans, we studied responsible pathways involved in the endoplasmic reticulum (ER) stress-induced cell death in neuroblastoma cells, SK-N-SH and its neuroblast-type subclone SH-SY5Y cells. A time-dependent induction of ER chaperons, glucose regulated protein (GRP)78 and GRP94, was observed after treatment with tunicamycin (TM), and cell death was also induced concomitantly in both cells. Although the pro-caspase-12-like protein was defined in both cells, a decrease in the protein was observed in only SH-SY5Y cells after exposure to TM. In contrast, pro-caspase-4 was detected in only SK-N-SH cells, and the cleaved-form was induced by the treatment with TM. A caspase-4 inhibitor, Z-LEVD-FMK attenuated TM-induced cell death in SK-N-SH cells. Calpain- and caspase-3-mediated proteolysis of alpha II-spectrin was also increased after the treatment with TM in both cells. A calpain inhibitor, calpeptin, repressed TM-induced cell death in only SK-N-SH cells. GADD153/C/EBP homologous protein (CHOP) was significantly induced after exposure to TM in only SH-SY5Y cells and RNA interference to GADD153/CHOP repressed TM-induced cell death. These results demonstrate that induction of GADD153/CHOP plays a pivotal role in mechanism of ER stress-induced cell death in SH-SY5Y cells, on the other hand, cleavage of pro-caspase-4 by activation of calpain play a crucial role in SK-N-SH cells. It is also suggested that the relevance of caspase-4 to ER stress is cell-specific even between human-origin cell lines.