Everolimus and exemestane represent a standard treatment for metastatic hormone receptor-positive/HER2-negative advanced breast cancer resistant to aromatase inhibitors. CA 15–3 serum levels detect soluble forms of MUC-1, a transmembrane oncoprotein aberrantly overexpressed in breast cancers. In clinical practice, CA 15–3 may be used to indicate treatment failure in the absence of readily measurable disease during cytotoxic therapy. In the targeted therapy era, it is important to note that the C-terminal subunit of MUC-1 interacts with PI3K/AKT pathway, inducting cell growth. Vice versa, the block of this pathway may influence MUC-1 expression and CA 15–3 serum levels. In this report, we emphasize the equivocal role of CA 15–3 serum levels in monitoring treatment with everolimus, suggesting a potential and intriguing role of a CA 15–3 increase as paradox predictive biomarker of response to everolimus.