Abstract: Objective To investigate the clinical efficacy of pertuzumab and trastuzumab (dual-targeted therapy) combined with chemotherapy or endocrine therapy in elderly patients with human epidermal growth factor receptor 2 (HER2)-positive breast cancer, and its impact on T lymphocyte subset effects. Methods A total of 138 elderly patients with HER2-positive breast cancer admitted to Qingdao Central Hospital of Rehabilitation University from March 2021 to September 2024 were included. They were assigned using a random number table method into two groups: a chemotherapy group (dual-targeted therapy + albumin-bound paclitaxel + carboplatin) and an endocrine therapy group (dual-targeted therapy + letrozole), with 69 patients in each. Both groups received 6 cycles of neoadjuvant dual-targeted therapy followed by surgical intervention. This study compared the objective remission rate (ORR), pathologic complete response (pCR), incidence of adverse reactions, quality of life using the Breast Cancer-Specific Quality of Life Questionnaire (QLQ-BR23), and T lymphocyte subsets (the proportion of CD3⁺T cells, CD4⁺T cells, and the CD4⁺T/CD8⁺T ratio) between the two groups of patients. Results The incidence of adverse reactions, such as neutropenia and leukopenia, was significantly lower in the endocrine therapy group than in the chemotherapy group (P＜0.05). After 6 cycles of treatment, the functional domain scores of the QLQ-BR23 increased, while the symptom domain scores decreased in both groups (P＜0.05). Furthermore, the proportions of CD3⁺T cells, CD4⁺T cells, and the CD4⁺T/CD8⁺T ratio were significantly increased after 6 treatment cycles compared to baseline in both groups. Notably, the increases in CD3⁺T cells, CD4⁺T cells, and CD4⁺T/CD8⁺T ratio were more pronounced in the endocrine therapy group compared to the chemotherapy group after 6 cycles of treatment (P＜0.05). Conclusion Dual-targeted therapy combined with endocrine therapy demonstrates comparable short-term efficacy to dual-targeted therapy combined with chemotherapy in elderly patients with HER2-positive breast cancer. However, the endocrine therapy combination is associated with fewer adverse reactions and leads to better improvement in patients, quality of life and immune function.