The multidrug resistance phenotype is one of the major problems in development of cancer cell resistanceto chemotherapy. Some natural compounds from medicinal plants have demonstrated promising capacity inenhancing anticancer effects in drug resistant cancer cells. We aimed to investigate whether mangiferin mighthave an ability to re-sensitize MCF-7 breast cancer cells previously treated with short-term doxorubicin in vitro,through the modulation of efflux transporters, P-glycoprotein (P-gp), MRP1 and BCRP. We exposed MCF-7 breastcancer cells pretreated with doxorubicin for 10 days to mangiferin (10, 25 or 50 μM) for 96 hours. Afterwards,we evaluated influence on cell viability and level of mRNA expression of P-gp, MRP1 and BCRP. Doxorubicingiven in combination with mangiferin at low concentrations (10 and 25 μM) failed to give significant reductionin cell viability, while at the highest concentrations, the combination significantly reduced cell viability. ThemRNA expression analysis of P-gp, MRP1 and BCRP showed that mangiferin had inhibitory effects on P-gp butno effects on MRP1 and BCRP. In conclusion, we suggest that mangiferin at high concentrations can be usedas chemosensitizer for doxorubicin therapy. This effect might be attributed by inhibitory effects of mangiferinon P-glycoprotein expression.