The xCT antiporter is known to be upregulated in 30 % of triple-negative breast cancer (TNBC) cell lines. The xCT-CD44 variant (CD44v) system regulates the levels of reactive oxygen species (ROS) in cancer cells and promotes tumor growth. Here, the role of this antiporter system in relation to chemotherapy was evaluated. MDA-MB-231 and MDA-MB-436 cells were transfected with lentiviral vectors expressing short hairpin RNA against xCT or CD44v. Following doxorubicin treatment, cellular proliferation was monitored, ROS were measured, and intracellular levels of cysteine and glutathione (GSH) were determined using liquid chromatography-mass spectrometry. A TNBC orthotopic tumor model was used to evaluate the impact of xCT-CD44v inhibition on doxorubicin efficacy in vivo. Doxorubicin treatment of TNBC cells caused increased expression of xCT through upregulation of CD44v. Consequently, the intracellular uptake of cystine increased, enabling rapid synthesis of GSH, and neutralization of doxorubicin-induced ROS. Suppression of xCT or CD44v impaired the defense against drug-induced oxidative stress, thereby sensitizing cells to doxorubicin. The importance of the xCT-CD44v in supporting tumor growth during doxorubicin treatment was also demonstrated in an in vivo tumor model of TNBC. These findings suggest that the antiporter system could serve as a target for increasing the anticancer efficacy of conventional therapy in patients with TNBC.