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Hypoxia has clinically been associated with resistance to chemotherapy. The aim of this study was to investigate whether hypoxia induces resistance to doxorubicin and mitoxantrone, two common drugs in cancer treatment, in MCF7 breast cancer cells, and SW1573 nonsmall lung cancer cells. In addition, the role of drug transporters Pgp, BCRP and MRP1 was analysed. Hypoxia induced resistance in MCF7 cells to mitoxantrone shifted the IC50value from 0.09 μM ±0.01 to 0.54 μM ±0.06 under hypoxia, whereas survival of MCF7 and SW1573 cells in the presence of doxorubicin was not altered. Accumulation of mitoxantrone and daunorubicin, a doxorubicin fluorescent homologue, appeared to be 5.3 and 3.2 times lower in MCF7 cells, respectively. Cytotoxicity assays showed no increased functionality of the drug transporters Pgp, BCRP and MRP1 under hypoxia. In addition, protein levels of these drug transporters were not changed. Medium of the MCF7 cells became more acidic under hypoxia thereby causing a decreased uptake of mitoxantrone. Hypoxia induces mitoxantrone resistance in MCF7 cells not mediated by the three major MDR transporters. Hypoxiainduced acidification may cause this resistance by decreased cellular uptake together with a lowered cytotoxicity due to pHdependent topoisomerase type II activity.