OBJECTIVE To investigate the combination of wild-type p53 (wtp53) gene substitution and adriamycin (ADM) on the lung cancer in vivo. METHODS The effect of combination of recombinant Adeno-wtp53 (rAd-p53) and ADM on reversing primary drug resistance to ADM was studied for the non-small cell lung cancer (NSCLC) in a nude mice model developed by subcutaneously transplanting with the 16HBE lung cancer cell line. Twenty four nude mice with loaded tumors were randomly divided into 4 groups (no treatment, rAd-p53 treatment alone, ADM treatment alone, combination of rAd-p53 plus ADM chemotherapy). The effect of rAd-p53 substitution and ADM on the drug sensitivity was evaluated. RESULTS In vivo studies on nude mice model transplanted with NSCLC showed that, rAd-p53 treatment alone suppressed tumor growth by 60.11% of the tumor weight and 85.4% by the volume (n = 6), while the combination of rAd-p53 with ADM suppressed tumor growth more significantly (82.32%, 99.5%, respectively, n = 6). The treatment with Adriamycin alone was less effective (35.4%, 73.9%, respectively, n = 6). CONCLUSION Combination of rAd-p53 and ADM significantly increased the sensitivity of NSCLC tumor graft to ADM, suggesting that the combination of replication-deficient wild p53 adenovirus with DNA-damaging drugs may increase the efficacy of chemotherapy in NSCLC and overcome primary drug resistance.