Background/aim: This study aimed to investigate the effect of chemoradiotherapy (CRT) on interferon-gamma (IFN-γ), interleukin-6 (IL-6), and tumor necrosis factor-alpha (TNF-α), which are critical markers of the clinical radiation response of patients with locally advanced non-small-cell lung cancer (NSCLC) and glioblastoma multiforme (GBM). Materials and methods: Thirty patients who were treated with CRT and 20 healthy controls were prospectively evaluated. Circulating levels of cytokines were measured by enzyme-linked immunosorbent assay procedure. Post-CRT and pre-CRT levels were compared. Results: Post-CRT, TNF-α and IFN-γ levels were significantly lower than pre-CRT levels in the NSCLC and GBM groups, respectively. The statistical analysis did not show any significant difference between the post- and pre-CRT IL-6 levels. However, the pre-CRT IL-6 levels in the GBM group and post-CRT IL-6 levels in the NSCLC group were significantly higher than those of the control group. Conclusion: CRT affected TNF-α levels in NSCLC and IFN-γ levels in GBM, with the levels of both decreasing significantly. The IL-6 levels of the post-CRT NSCLC group were higher than those of the post-CRT GBM group. Irradiation-induced IL-6 may be responsible for tumor regrowth. Therefore, treatment with IL-6 inhibitors could be a potential therapeutic strategy for sensitizing NSCLC to irradiation in the clinic.