Triple-negative breast cancer (TNBC) is aggressive, highly metastatic, and associated with poor patient prognosis. Sialyl-Lewis X and A (sLesup.X/A ) are sugars with important roles in cell signalling and metastasis. We aimed to describe the relevance of sLesup.X/A in TNBC patients and its association with other biomarkers. We identified that sLesup.X/A negatively correlated with cytokeratins, structural proteins present at the cell cytoskeleton, and are involved in cell attachment, by using patient tissues, cell lines, and datasets. Our data suggests that sLesup.X/A is decorating proteins such as integrin alpha 6, deregulating cell signalling responsible for hemidesmosome formation, impacting cell adhesion, and promoting metastatic behaviour. This work highlights sLesup.X/A as an important biomarker behind TNBC malignancy to target and treat this breast cancer type. Triple-negative breast cancer (TNBC) encompasses multiple entities and is generally highly aggressive and metastatic. We aimed to determine the clinical and biological relevance of Sialyl-Lewis X and A (sLesup.X/A )—a fucosylated glycan involved in metastasis—in TNBC. Here, we studied tissues from 50 TNBC patients, transcripts from a TNBC dataset from The Cancer Genome Atlas (TCGA) database, and a primary breast cancer cell line. All 50 TNBC tissue samples analysed expressed sLesup.X/A . Patients with high expression of sLesup.X/A had 3 years less disease-free survival than patients with lower expression. In tissue, sLesup.X/A negatively correlated with cytokeratins 5/6 (CK5/6, which was corroborated by the inverse correlation between fucosyltransferases and CK5/6 genes. Our observations were confirmed in vitro when inhibition of sLesup.X/A remarkably increased expression of CK5/6, followed by a decreased proliferation and invasion capacity. Among the reported glycoproteins bearing sLesup.X/A and based on the STRING tool, α6 integrin showed the highest interaction score with CK5/6. This is the first report on the sLesup.X/A expression in TNBC, highlighting its association with lower disease-free survival and its inverse crosstalk with CK5/6 with α6 integrin as a mediator. All in all, sLesup.X/A is critical for TNBC malignancy and a potential prognosis biomarker and therapeutic target.