Endoplasmic reticulum stress-mediated apoptosis plays an important role in the destruction of pancreatic beta-cell, and contributes to the development of type 1 diabetes. The chaperone molecule, glucose regulated proteins 78 (GRP78), is required to maintain ER function during toxic insults. In this study, we investigated the effect of GRP78 on the beta-cell apoptosis. We first measured GRP78 protein expression in different phase of streptozotocin-affected beta-cell by immunoblotting analysis. An insulinoma cell line, NIT-1, transfected with GRP78 was established, named NIT-GRP78, and used to study apoptosis, which was induced by streptozotocin or inflammatory cytokines. Apoptosis of NIT-1 or NIT-GRP78 cells was detected by flow cytometry, the transcription of C/EBP homologous protein (CHOP) was monitored by real-time PCR, the concentration of nitric oxide and the activity of superoxide dismutase were measured by colorimetric method. We found that, in comparison to NIT-1 cells, NIT-GRP78 cells responded to the streptozotocin or cytokines treatments with decreased concentration of nitric oxide, but increased activity of superoxide dismutase. In addition, the level of CHOP was also decreased in the NIT-GRP78 cells, which may mediate the resistance of the GRP78 overexpressed NIT-1 cells from apoptosis. Finally, we found that NIT-GRP78 cells were also more resistant than NIT-1 cells to cytotoxic T lymphocyte (CTL) specific killing detected by flow cytometry through target cells expressing green fluorescent protein cultured with effector cells and finally stained with propidium iodide. The data suggest that modulating GRP78 expression could be useful in preventing pancreatic beta-cell from the immunological destruction in type 1 diabetes individuals.