Although an endoplasmic reticulum (ER) induction by calcium-channel blocker has been reported, the mechanism of ER stress-mediated apoptosis by nicardipine is unknown. Here, we demonstrated induction of apoptosis by nicardipine in PC12 cells. It was accompanied by the formation of apoptotic bodies via activation of ER-stress sensor, inositol-requiring enzyme 1 (IRE1). IRE1 induces the downregulation of key anti-apoptotic Bcl-2 expression in apoptosis. However, the altered expression of ER chaperones was not observed following nicardipine treatment. The results suggest that insight into the molecular mechanisms underlying nicardipineinduced apoptosis may facilitate the reduction of side effects and active treatment.