Background <p>The combination of trastuzumab and chemotherapeutic drugs improves the prognosis of patients with metastatic disease and reduces the mortality. However, trastuzumab resistance has limited the remarkable improvement of this drug. The carboxyl-terminal modulator protein (CTMP) is involved in the regulation of various cancers through positive or negative regulation of Akt. In the HER2-positive SkBR3 breast cancer cell line, CTMP overexpression increases Akt phosphorylation at Thr308 and Ser473. Therefore, CTMP might mediate trastuzumab resistance. The main objective of the paper is to explore the role of CTMP in trastuzumab efficacy in HER2 + metastatic breast cancer (MBC) patients.</p> Patients &amp; methods <p>Ninety-six patients received trastuzumab in combination with chemotherapy or hormonal therapy until disease progression. The overall responses of all the patients were assessed as follows: complete response (<i>n</i> = 5), partial response (<i>n</i> = 36), stable disease (<i>n</i> = 24), and progressive disease (<i>n</i> = 31).</p> Results <p>Immunohistochemistry (IHC) staining was carried out to identify CTMP expression in formalin-fixed paraffin-embedded (FFPE) archival tissue blocks. 58 cases had high CTMP expression levels and 38 cases had low CTMP expression levels. The Mann-Whitney U test showed that CTMP expression was markedly higher in trastuzumab non-responders than in trastuzumab responders (<i>P</i> = 0.039). In addition, high CTMP expression was a strong and independent predictor of shorter recurrence-free survival in patients with metastatic breast cancer, as determined by the Kaplan-Meier method.</p> Conclusions <p>Based on the results, further examination of CTMP in HER2-enriched (MBC) tissue samples could be helpful in predicting patients at risk of tumor progression and trastuzumab resistance.</p>