Background: HER2-positive metastatic breast cancer has a high risk of brain metastases, leading to poor survival. Our phase 2 PERMEATE trial (NCT03691051) has shown the promising efficacy of pyrotinib (an irreversible pan-HER receptor tyrosine kinase inhibitor) plus capecitabine in patients with HER2-positive metastatic breast cancer and brain metastases, with an intracranial objective response rate of 74.6% (44/59) and 42.1% (8/19) in patients with radiotherapy-naïve (cohort A) and radiotherapy-treated (cohort B) brain metastases, respectively. Here we updated 3-year follow-up results from this trial. Methods: Patients received 21-day cycles of pyrotinib (400 mg orally once daily) and capecitabine (1000 mg/m² orally twice daily on days 1-14) until disease progression or intolerable toxicity. Patients with progression isolated to the brain lesions would be withdrawn from the study, but could resume on the study treatment after local surgery or radiotherapy until the second progression at any site or death, at the discretion of the investigator. Intracranial and extracranial responses were assessed according to the Response Evaluation Criteria In Solid Tumors, version 1.1. Progression-free survival (PFS; time from the initiation of the study treatment to progression at any site or any-cause death), overall survival (OS), and second PFS (PFS2; time from progression isolated to the brain lesions to the second progression at any site) were reported. Results: By the data cutoff date on February 8, 2023, the median follow-up duration was 40.5 months (95% CI: 39.0-43.0). Cohort A showed a median PFS of 10.7 months (95% CI: 7.6-14.9) and a median OS of 35.9 months (95% CI: 25.1-not reached). The 1-year and 3-year OS rates were 84.6% (95% CI: 76.0-94.4) and 49.8% (95% CI: 38.0-64.6), respectively. Fifteen patients with progression isolated to the brain lesions in cohort A resumed on the study treatment after local treatment, with a median PFS2 of 10.4 months (95% CI: 6.5-19.7). Cohort B showed a median PFS of 5.6 months (95% CI: 5.4-11.9) and a median OS of 31.4 months (95% CI: 22.0-not reached). The 1-year and 3-year OS rates were 78.9% (95% CI: 64.0-99.6) and 29.1% (95% CI: 13.0-60.4), respectively. Conclusions: These findings suggest the long-term survival benefit provided by pyrotinib plus capecitabine in patients with HER2-positive metastatic breast cancer and brain metastases, especially in the radiotherapy-naive cohort. Clinical trial information: NCT03691051.