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Breast cancer (BC) exhibits significant heterogeneity and complexity and is leading causes of mortality in women globally. Paclitaxel (PTX) is commonly utilized as the primary medication for BC. However, the resistance of BC to PTX poses a significant challenge in clinical treatment. This study aimed at to explore whether carboxy-terminal domain small phosphatase like 2 (CTDSPL2) affected PTX resistance in BC cells. PTX resistant BC cell lines, including MCF-7/PTX and MDA-MB-231/PTX, were developed by continuously increasing PTX concentration, and we found that CTDSPL2 was upregulated in BC cells with PTX resistance. Loss-of-function studies showed that CTDSPL2 knockdown caused a decrease in cytotoxicity and proliferative ability in PTX-resistant BC cells, as well as enhanced cell apoptotic rate and DNA damage. The results from nanoparticle tracking analysis (NTA) indicated that CTDSPL2 knockdown also suppressed the secretion of extracellular vesicles. In vivo tumorigenesis assays showed that CTDSPL2 downregulation inhibited tumorigenicity of nude mice injecting with PTX-resistant BC cells. Co-immunoprecipitation (Co-IP) assay demonstrated the binding between CTDSPL2 and SCY1-like pseudokinase 1 (SCYL1). The increased level of SCYL1 phosphorylation evoked by CTDSPL2 knockdown in PTX-resistant cancer cells was blocked after mutating the serine 754 site of SCYL1 to alanine. In conclusion, the present study identifies CTDSPL2 as a new factor in BC that plays an essential role in PTX-resistant BC cells through the regulation of SCYL1 phosphorylation.