Background: ${alpha}$-Lipoic acid (${alpha}$-LA) has been studied as an anticancer agent as well as a therapeutic agent for diabetes and obesity. We performed this study to evaluate the anticancer effects and mechanisms of ${alpha}$-LA in a lung cancer cell line, A549. Materials and Methods: ${alpha}$-LA-induced apoptosis of A549 cells was detected by fluorescence-activated cell sorting analysis and a DNA fragmentation assay. Expression of apoptosis-related genes was analyzed by western blot and reverse transcription.polymerase chain reaction analyses. Results: ${alpha}$-LA induced apoptosis and DNA fragmentation in A549 cells in a dose- and time-dependent manner. ${alpha}$-LA increased caspase activity and the degradation of poly (ADP-ribose) polymerase. It induced expression of endoplasmic reticulum (ER) stress-related genes, such as glucose-regulated protein 78, C/EBP-homologous protein, and the short form of X-box binding protein-1, and decreased expression of the anti-apoptotic protein, X-linked inhibitor of apoptosis protein. Reactive oxygen species (ROS) production was induced by ${alpha}$-LA, and the antioxidant N-acetyl-L-cysteine decreased the ${alpha}$-LA-induced increase in expression of apoptosis and ER stress-related proteins. Conclusion: ${alpha}$-LA induced ER stress-mediated apoptosis in A549 cells via ROS. ${alpha}$-LA may therefore be clinically useful for treating lung cancer.