It is reported that the agonistic antibodies against death receptors 4 and 5 (DR4, DR5) are cytotoxic to various cancer cells. In the present study, the sensitivity of five human lung cancer cell lines to previously reported AD5‐10 agonistic antibody against DR5 were investigated. Of these cell lines, A549 and small cell lung cancer showed a moderate sensitivity to AD5‐10 and three other cell lines were resistant. Cell line H460 is resistant to AD5‐10 despite a high level of cell‐surface DR5 expression. We demonstrated that the resistance of H460 cells to AD5‐10 was not related to the expression level of DR5, but the expression and cleavage of c‐FLIPL in the cells. Inhibition of endogenous c‐FLIPL expression by siRNA significantly enhanced AD5‐10‐induced cell death in these lung cancer cells. We further showed that this sensitizing effect was associated with decreased expression of Bcl‐2 family proteins Bid and Bcl‐XL, change of mitochondrial membrane potential, release of cytochrome c from mitochondria, and caspase activation. Therefore, these data provide evidence that c‐FLIPL is involved in the resistance of lung cancer cells to AD5‐10‐induced apoptosis. Moreover, immunohistochemistry on paraffin‐embedded tissue revealed that c‐FLIPL was expressed in 87.9% (29 of 33) of lung carcinoma tissues from the patients, but little in tissues from normal controls. This suggests that inhibition of c‐FLIPL expression might be a potential strategy for lung cancer therapy, especially for those lung cancers resistant to the agonistic antibody against death receptors. (Cancer Sci 2009; 100: 940–947)