TRAIL‑R2 (DR5), one of the death receptors, can activate the extrinsic apoptosis pathway, while cellular FLICE‑inhibitory protein (c‑FLIP) can inhibit this pathway. Both of them play important roles in the occurrence and development of most tumors. To date, there is no relevant report concerning the relationship between expression of DR5 and c‑FLIP protein and clinicopathological/prognostic implications in patients with non‑small cell lung cancer (NSCLC) treated with surgical resection and chemotherapy. Thus, the aim of the present study was to investigate the potential prognostic significance of DR5 and c‑FLIP in NSCLC patients and their predictive roles in the chemotherapeutic response. In the present study, DR5 and c‑FLIP were detected by immunohistochemistry (IHC) in tissue microarrays of NSCLC. The results showed that the expression levels of DR5 and c‑FLIP were significantly higher in lung squamous cell carcinoma (SCC) and lung adenocarcinoma (ADC) tissues compared with levels noted in the non‑cancerous control lung tissues (all P<0.05). In addition, DR5 expression was significantly increased in lung ADC (P<0.001), whereas, c‑FLIP was higher in lung SCC (P<0.001) and smoker patients with clinical stage III (P=0.019, P=0.016, respectively). In addition, NSCLC patients with overexpression of DR5 and loss of c‑FLIP expression exhibited a higher overall survival (OS) rate as determined by Kaplan‑Meier analysis (P=0.029, P=0.038, respectively). Multivariate analysis confirmed that high expression of DR5 and loss of c‑FLIP expression were independent favorable prognostic factors for NSCLC patients (P=0.016, P=0.035, respectively). In conclusion, overexpression of DR5 and loss of c‑FLIP expression may serve as novel favorable prognostic biomarkers for NSCLC patients treated with chemotherapy after radical resection and used as predictors for tumor response to chemotherapy drugs.