Objective To explore the efficacy and safety of pyrotinib combined with letrozole in the treatment of human epidermal growth factor receptor 2 (HER2)-positive and estrogen receptor (ER)-positive metastatic breast cancer.Methods In this study, a single arm design was used, and 86 patients with HER2-positive and ER-positive metastatic breast cancer were planned to receive pyrotinib combined with letrozole. The subjects entered the trial period immediately after being enrolled, and received continuous treatment with pyrotinib and letrozole until the disease progressed, or the toxicity was intolerable, or the informed consent was withdrawn, or the investigator judged that the drug must be terminated. The imaging evaluation was conducted according to the response evaluation criteria in solid tumors 1.1 (RECIST1.1), and the evaluation result of the research center was the final result. The primary end point was clinical benefit rate (CBR), and secondary key indicators included the effectiveness indicators [objective response rate (ORR), progression-free survival (PFS), overall survival (OS)] and safety indicators (according to NCI-CTC AE 4.03 standard).Results Up to the interim summary, 30 subjects were enrolled in the group, including one patient with screening failure and four patients with disease progression (PD). Twelve patients benefited clinically, including one patient with complete remission (CR), four patients with partial remission (PR) and seven patients with stable disease (SD). Diarrhea was the most common adverse reaction, with 90% of patients suffering from diarrhea and 3 patients suffering from grade III diarrhea. Other adverse reactions included hyperuricemia, vomiting, and decreased leukocyte count.Conclusion The mid-term results suggest that in patients with HER2-positive and ER-positive metastatic breast cancer, pyrotinib combined with letrozole shows an encouraging anti-tumor activity and good tolerance, which is expected to become a treatment option for this kind of disease.