Abstract: Objective To investigate the differences in clinicopathological characteristics and prognosis between triple positive breast cancer and human epidermal growth factor receptor-2 (Her-2) overexpressing breast cancer, and to reveal the heterogeneity of these two subtypes, in order to provide data support for the selection of diagnostic and treatment options for these two types of breast cancer. Methods A total of 179 patients who were diagnosed with triple positive breast cancer and 161 patients with Her-2 overexpressing breast cancer in the Affiliated Hospital of Xuzhou Medical University from July 2016 to September 2022 were selected. Their clinical data were retrospectively analyzed using the case-control approach, in order to investigate their clinicopathological characteristics and prognosis. Results Compared with Her-2 overexpressing breast cancer, triple positive breast cancer had an earlier age of onset, and occurred more frequently in premenopausal patients, with late TNM stages, which was easy to invade the vasculature and nerves, and showed high expression of proliferating cell nucleus antigen 67 (Ki67). The overall survival (OS) and progression-free survival (PFS) were higher in triple positive breast cancer patients than those in Her-2 overexpression patients. Conclusions Patients with triple positive breast cancer show superior prognosis to those with Her-2 overexpression. However, it has the disadvantage of drug resistance due to the cross-talk between its targeted therapy and endocrine therapy, which needs to be further explored.