Cisplatin　is　ranked　as　one　of　the　most　powerful　and　commonly　prescribed　anti-tumor　chemotherapeutic　agents　which　improve　survival　in　many　solid　tumors　including　non-small　cell　lung　cancer.　However,　the　treatment　of　advanced　lung　cancer　is　restricted　due　to　chemotherapy　resistance.　Here,　we　developed　and　investigated　survivin　promoter　regulating　conditionally　replicating　adenovirus　(CRAd)　for　its　anti-tumor　potential　alone　or　in　combination　with　cisplatin　in　two　lung　cancer　cells,　H23,　H2126,　and　their　resistant　cells,　H23/CPR,　H2126/CPR.　To　measure　the　expression　of　genes　which　regulate　resistance,　adenoviral　transduction,　metastasis,　and　apoptosis　in　cancer　cells,　RT-PCR　and　Western　blotting　were　performed.　The　anti-tumor　efficacy　of　the　treatments　was　evaluated　through　flow　cytometry,　MTT　and　transwell　assays.　This　study　demonstrated　that　co-treatment　with　cisplatin　and　CRAd　exerts　synergistic　anti-tumor　effects　on　chemotherapy　sensitive　lung　cancer　cells　and　monotherapy　of　CRAd　could　be　a　practical　approach　to　deal　with　chemotherapy　resistance.　Combined　treatment　induced　stronger　apoptosis　by　suppressing　the　anti-apoptotic　molecule　Bcl-2,　and　reversed　epithelial　to　mesenchymal　transition.　In　conclusion,　cisplatin　synergistically　increased　the　tumor-killing　of　CRAd　by　(1)　increasing　CRAd　transduction　via　enhanced　CAR　expression　and　(2)　increasing　p53　dependent　or　independent　apoptosis　of　lung　cancer　cell　lines.　Also,　CRAd　alone　proved　to　be　a　very　efficient　anti-tumor　agent　in　cancer　cells　resistant　to　cisplatin　owing　to　upregulated　CAR　levels.　In　an　exciting　outcome,　we　have　revealed　novel　therapeutic　opportunities　to　exploit　intrinsic　and　acquired　resistance　to　enhance　the　therapeutic　index　of　anti-tumor　treatment　in　lung　cancer.