Background: The BRAF inhibitors vemurafenib and dabrafenib have demonstrated antitumor activity in patients with metastatic BRAFV600-mutant melanoma. However, patients with BRAF wild-type, in particular patients with aggressive NRAS-mutant melanoma, do not benefit. In a phase 2 trial, the MEK inhibitor binimetinib showed activity in patients with NRAS-mutant melanoma with overall response rates of >20%. In a previous study, we showed that the BRAF inhibitor vemurafenib induces apoptosis in BRAFV600-mutant melanoma cells through a mechanism involving induction of endoplasmic reticulum (ER) stress. ER stress induction appeared to be an off-target effect of vemurafenib that remarkably enhances its pro-apoptotic activity in BRAFV600-mutant melanoma. Methods: In this study, we investigated whether it is possible to take advantage of ER stress induction to establish effective combination therapies for patients with NRAS-mutant melanoma. Results: BRAF-mutant and NRAS-mutant metastatic melanoma cell lines were treated with the BRAF inhibitors vemurafenib, dabrafenib and LGX818, and the classical ER stress inducer thapsigargin, and were subjected to electron microscopy. Of note, LGX818 induced morphological features of ER stress, including a significant dilation of the ER in both BRAF-mutant and NRAS-mutant melanoma cell lines. As expected, LGX818 inhibited phosphorylation of ERK and growth and induced apoptosis in BRAF-mutant but not in NRAS-mutant melanoma cells. However, LGX818 significantly enhanced growth inhibition and apoptosis induced by the MEK inhibitor binimetinib in NRAS-mutant melanoma cells. Moreover, LGX818 in combination with binimetinib induced the expression of the ER stress-related factors p8, ATF4, ATF3, CHOP and TRB3 in NRAS-mutant melanoma cells. siRNA inhibition of ATF4 reduced melanoma cell apoptosis induced by LGX818 combined with binimetinib. Conclusions: These data suggest that the BRAF inhibitor LGX818 induces endoplasmic reticulum stress and potentiates the antitumor activity of MEK inhibitors in NRAS-mutant melanoma.