Macrophages are important in the host's immune defense against pathogens. However, recent evidence has demonstrated that macrophages are also involved in the development of disease, including cancer. Therefore, it is important to regulate apoptosis in tumor‑related macrophages for effective cancer treatment. In the present study, the effect of endoplasmic reticulum (ER) stress on apoptosis induction was examined in human monocytic cell‑derived macrophages. Radiation therapy in cancer results in irradiating macrophages as well as cancer cells in the tumor microenvironment. Since ER stress has been demonstrated to sensitize cancer cells to radiation, it was hypothesized that ER stress may induce a similar effect in macrophages. Therefore, the effect of combination treatment with ER stress inducers and ionizing radiation on macrophage apoptosis was examined. Treatment of macrophages with ER stress inducers thapsigargin and tunicamycin, enhanced unfolded protein responses, including phosphorylation of eukaryotic initiation factor 2‑α and increased expression of binding immunoglobulin protein. Furthermore, treatment with thapsigargin and tunicamycin induced apoptosis in macrophages compared with untreated cells, although ionizing radiation did not. The thapsigargin-induced apoptosis in macrophages was demonstrated to be caspase‑3‑dependent. Finally, combination treatment with thapsigargin and ionizing radiation, did not result in any significant change in macrophage apoptosis. The present study demonstrated that ER stress regulated apoptosis in radioresistant macrophages and that ionizing radiation had no added effect on ER stress‑induced apoptosis in macrophages.