Background: In a previous study, we showed that the pan-RAF inhibitor sorafenib induces upregulation of endoplasmic reticulum (ER) stress-related genes and apoptosis in melanoma cells in vitro. Methods: In this study, we posed the question whether PLX4032, which selectively inhibits the BRAFV600E kinase and demonstrated potent antitumor activity in melanoma patients with the BRAFV600E mutation, induces ER stress-mediated apoptosis in metastatic melanoma cells harboring a BRAFV600E mutation. Results: The BRAFV600E kinase inhibitor PLX4032 inhibited growth, induced apoptosis and upregulated the ER stress-related genes p8, CHOP, ATF4, ATF3 and TRB3 exclusively in BRAFV600E mutated melanoma cell lines. Furthermore, electron microscopy showed morphological features of ER stress, in particular significant swelling of the ER lumen of BRAFV600E melanoma cells treated with PLX4032 compared with BRAFV600E melanoma cells treated with vehicle. siRNA inhibition of p8 reduced melanoma cell apoptosis induced by PLX4032, overexpression of p8 enforced melanoma cell apoptosis induced by PLX4032. Furthermore, classical ER stress inducers such as thapsigargin and tunicamycin potently inhibited growth, induced apoptosis and suppressed invasive tumor growth of melanoma cells. Moreover, both thapsigargin and tunicamycin upregulated p8 and CHOP and induced apoptosis in PLX4032-resistant melanoma cells. Conclusions: These data suggest that the BRAFV600E kinase inhibitor PLX4032 induces apoptosis in BRAFV600E melanoma cells through upregulation of ER stress-related genes, and that melanoma cells which acquired resistance to PLX4032 may be sensitive to agents which induce ER stress-mediated apoptosis through a different mechanism.