Abstract Hypoxia frequently occurs in solid tumors and is known to contribute to chemotherapy resistance. However, the mechanisms leading to chemotherapy resistance are not entirely known. We investigated hypoxia-induced resistance to cisplatin in NSCLC cell lines. We show that chronic moderate hypoxia induced resistance to cisplatin in NSCLC cells without involvement of selection pressure. Our data suggest that stabilization of the hypoxia-inducible factor 1 alpha and down-regulation of the pro-apoptotic protein BAX play a role in this process. Furthermore, we provide evidence that hypoxia-induced resistance to cisplatin is not due to the reduced growth rate of cancer cells under hypoxic conditions.