Background and Aims Neoadjuvant chemotherapy is an important treatment strategy for breast preservation after downstaging and improving overall cure rates in early high-risk or locally advanced breast cancer. The selection of patients and the development of treatment plans for neoadjuvant chemotherapy depend on molecular subtypes. However, there is currently a lack of research on the efficacy of neoadjuvant chemotherapy and differences in survival prognosis based on the expression levels of human epidermal growth factor receptor 2 (HER-2) in breast cancer. Therefore, this study was performed to compare the efficacy of neoadjuvant chemotherapy and differences in survival prognosis among breast cancer patients with different levels of HER-2 expression, and identify the factors influencing the efficacy of neoadjuvant chemotherapy and survival prognosis, so as to provide valuable insights for the selection of patients and development of treatment plans for clinical neoadjuvant chemotherapy.Methods The data of breast cancer patients who underwent neoadjuvant chemotherapy and radiacal mastectomy in the Department of Breast Surgery, Xiangya Hospital, Central South University, from January 2018 to May 2022 were retrospectively analyzed. The differences in clinicopathologic characteristics among patients with different HER-2 expression levels (zero-expression, low-expression, overexpression) were compared. Logistic regression analysis was used to identify independent factors influencing pathological complete response (pCR). Kaplan-Meier method was employed to estimate survival curves, and the Log-rank test was used to compare differences in survival rates. Cox regression analysis was conducted to identify independent prognostic factors.Results A total of 601 patients were included, among whom 231 (38.4%) had HER-2 zero-expression, 137 (22.8%) had HER-2 low-expression, and 233 (38.8%) had HER-2 overexpression. Compared to patients with HER-2 zero-expression and HER-2 overexpression, patients with HER-2 low-expression had higher BMI value, fewer cases of family history of tumors, lower histological grades, and a higher proportion of hormone receptor (HR) positivity; the degree of tumor fibrosis was significantly lower in patients with HER-2 overexpression compared to those with HER-2 zero-expression and HER-2 low-expression (all P<0.05). Among patients with HER-2 low-expression, the HR-negative subgroup had larger tumor size, higher histological grades, and higher Ki-67 level compared to the HR-positive subgroup (all P<0.05). In the entire cohort, HER-2 expression level, pCR, and clinical lymph node stage (cN) were independent factors influencing disease-free survival (DFS) (all P<0.05). Patients with HER-2 overexpression had significantly higher pCR and DFS rates after neoadjuvant chemotherapy compared to those with HER-2 low-expression and HER-2 zero-expression (all P<0.05), but there was no significant difference in neoadjuvant chemotherapy pCR and DFS rates between patients with HER-2 low-expression and HER-2 zero-expression (all P>0.05). Tumor fibrosis and estrogen receptor (ER) status were independent factors influencing pCR in HER-2 zero-expression breast cancer, while stromal tumor-infiltrating lymphocytes (sTILs) were independent factors influencing pCR in HER-2 low-expression breast cancer, and tumor fibrosis and ER status were independent factors influencing pCR in HER-2 overexpression breast cancer (all P<0.05).Conclusion Neoadjuvant chemotherapy is more effective in breast cancer patients with HER-2 overexpression compared to those with HER-2 zero-expression and low-expression. ER status, fibrosis degree, and sTILs level are independent factors influencing pCR in patients with HER-2 zero-expression and low-expression, while ER status and fibrosis degree are independent factors influencing pCR in patients with HER-2 overexpression.