Purpose <p>Trophoblast cell surface antigen 2 (TROP-2) is a type I transmembrane glycoprotein that is expressed on the cell surface. It is overexpressed in various epithelial malignancies. Due to its protumoral biological effects and its role as a target receptor for antibody–drug conjugates, TROP-2 is of particular clinical interest. This study aims to investigate the relationships between TROP-2 expression, clinicopathological parameters, and response to neoadjuvant chemotherapy in invasive breast carcinomas.</p> Methods <p>TROP-2 expression was evaluated by immunohistochemically from 211 cases of invasive breast carcinoma. The H-score was used in the TROP-2 assessment. Cases with a score of 0-200 were considered low, and cases with a score above 200 were considered high TROP-2 expression.</p> Results <p>High TROP-2 expression was significantly associated with HER2 negativity (<i>p</i> = 0.019), lymph node metastasis (<i>p</i> = 0.016), and a poor response to neoadjuvant chemotherapy (RCB-II/III) (<i>p</i> = 0.01). Multivariate analysis revealed that molecular subtype, stromal tumor-infiltrating lymphocytes, and high TROP-2 expression were independent predictors of neoadjuvant chemotherapy response.</p> Conclusion <p>High TROP-2 expression was found to be associated with adverse clinicopathological parameters and poor response to neoadjuvant chemotherapy, and was identified as an independent predictive biomarker for neoadjuvant response. The lower pathological complete response rates observed in luminal B molecular subtype breast carcinomas with high TROP-2 expression suggest that TROP-2-targeting agents should be investigated more thoroughly in the neoadjuvant therapy setting, particularly in LB subtype cases. Furthermore, assessing TROP-2 expression in each case will aid in optimal patient selection for treatment and contribute to the personalization of oncological therapy.</p>