Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL), which is being evaluated clinically for cancer therapy, selectively induces apoptosis in tumor cell lines without causing toxicity to normal cells. However, its therapeutic potential is limited by occurring resistance in a majority of lung carcinoma, breast and prostate cells. Various chemotherapeutic drugs have been found to enhance TRAIL-induced apoptosis. The objective of this study was to examine whether non-small cell lung cancer (NSCLC) cell line A-549, one of the most drug-resistant tumor cells in human, can be sensitized by doxorubicin (DOX) to TRAIL-mediated apoptosis. We show that DOX and recombinant human TRAIL (TRAIL) have a synergistic cytotoxic effect against A-549 cells in vitro. However, no obvious antitumor effects were observed in A-549 tumor bearing nude mice treated by TRAIL alone, DOX alone or both agents, suggesting that further works should be carried to improve the efficacy of combined treatment of DOX and TRAIL.