Objectives Sodium salicylate (NaSal) can disturb cell viability by affecting the activity of multiple cellular molecules. In this work, we investigated the involvement of stress-responsive kinase GCN2 in regulating cell death and expression of stress genes in mouse embryonic fibroblasts (MEFs) upon exposure to NaSal. Methods Cell viability was assayed using the 3-(4,5-dimethylthiazol-2yl)-2,5- diphenyltetrazolium bromide (MTT) method, and apoptosis was evaluated by annexin V and propidium iodide staining. A polymerase chain reaction (PCR) array approach was used to analyse differential expression of a panel of 84 endoplasmic reticulum (ER) stress-associated genes. Gene reporter assays were carried out to determine activity of ER stress element (ERSE), and the protein levels of activating transcription factor 6 (ATF6) and C/EBP homologous protein (CHOP) were determined by western blot. Key findings NaSal treatment resulted in reduction of cellular viability and induction of apoptosis in wild-type but not Gcn2-/- cells. Many genes with important functions in protein synthesis/degradation, transcriptional regulation and apoptosis were induced by NaSal and most of these were dependent on GCN2. The activation of ERSE within Ddit3 and the production of CHOP and ATF6 induced by NaSal required GCN2. Conclusions Our data provide evidence for the involvement of GCN2 in apoptosis and gene expression triggered by NaSal, and contributes to the understanding of molecular events occurring in NaSal-treated cells.