Abstract: Objective:To investigate the mechanism of endoplasmic reticulum (ER) stress-induced chemoresistance to cisplatin in gastric cancer cells. Methods:ER stress models were established in both BGC823 and SGC 7901gastric cancer cells. The expression of GRP78, an ER stress marker, was examined by Western blot analysis. Moreover, whether ER stress can decrease the sensitivity of gastric cancer cells to cisplatin and activate P 38was explored by flow cytometry and Western blot analysis, respectively. Whether ER stress-induced chemoresistance to cisplatin can be abrogated by blocking P 38activity in gastric cancer was also elucidated using flow cytometry. Results:GRP 78protein expression markedly increased after treating BGC823 and SGC 7901gastric cancer cells with tunica-mycin (TM) or thapsigargin (TG) for8, 16, and 24h (P<0.05), compared with that in the group treated for 0 h. The apoptotic rates of TM- (or TG)-, cisplatin-, and TM (or TG) plus cisplatin-treated groups significantly increased ( P<0.05) in both BGC 823 and SGC 7901 gastric cancer cells compared with the rate in the control group. The apoptotic rate of TM (or TG) plus cisplatin-treated group signifi-cantly decreased (P<0.05) in both BGC 823 and SGC 7901gastric cancer cells compared with that of the cisplatin-treated group. Com -pared with the group treated for 0 h, phospho-P38expression markedly increased after treating BGC 823 and SGC 7901gastric ca ncer cells with TM (or TG) for 8, 16, and 24h (P<0.05). No difference in P 38protein expression was observed between each group in both BGC823 and SGC 7901gastric cancer cells (P>0.05). Both P 38inhibitors, either SB203580or PD169316, can inhibit the activation of P38. The inhibition of P38activity can overcome ER stress-induced chemoresistance to cisplatin in gastric cancer cells ( P<0.05). Con -clusion: ER stress can trigger the chemoresistance to cisplatin by activating P38in gastric cancer cells.