Breast cancer is one of the most common cancers in women worldwide. Tamoxifen (TAM) provided a successful treatment for ER-positive (ER+) breast cancer for many years. However, ER+ patients with metastatic diseases respond poorly to TAM therapy and many initial responders eventually relapse. Emerging evidence indicates that long non-coding RNAs (lncRNAs) may have a critical role in the regulation of cellular processes such as cancer progression and metastasis, though the function of lncRNAs in TAM-resistance is still unclear. To investigate the role of CCAT2 in the development of resistance to TAM treatment of breast cancer, we established TAM-resistant models in MCF-7 and T47D cells. The present study demonstrates that TAM-resistant cells show a higher level of CCAT2 expression compared with TAM-sensitive cells. Biologically, CCAT2 knockdown could inhibit proliferation and induce apoptosis in TAM-resistant cells exposed to TAM. Furthermore, knockdown of CCAT2 improves the sensitivity to TAM in TAM-resistant cells. Overall, the study results provide a novel therapeutic approach for TAM-resistant patients through depleting CCAT2 expression.