Background: A single-arm prospective phase II trial to was conducted evaluate the efficacy and safety of oral metronomic capecitabine combined with pyrotinib in human epidermal growth factor receptor 2-positive (HER2 positive) metastatic breast cancer (MBC) patients. Methods: HER2-positive patients received oral metronomic capecitabine 500 mg three times daily and pyrotinib 400 mg. The primary endpoint was progression-free survival (PFS). Other endpoints included objective response rate (ORR), clinical benefit rate (CBR), overall survival (OS), and safety. Results: 50 patients with HER2-positive MBC were enrolled, and one was excluded due to medication irregularities. The median PFS and OS were 11.9 months (95%CI 8.8-14.6) and 29.3 months (95%CI 24.4-34.8) respectively. ORR was 34.7%, and CBR was 81.6% with 2 CR (4.1%), 15 PR (30.6%) and 23 SD (46.9%). The mPFS in first- or second-line treatment was 12.2 months. The most frequent treatment-related adverse complications included hand-foot syndrome, diarrhea, vomiting and nausea. Grade 3 adverse events occurred in 15 (30.6%) patients and included hand-foot syndrome (12.2%), diarrhea (12.2%), vomiting (4.1%), and nausea (2.0%). Grade 4 adverse event of diarrhea (2.0%) was observed in one case. Conclusions: The combination of metronomic capecitabine and pyrotinib is a promising regimen with competitive efficacy and improved tolerability in HER2-positive metastatic breast cancer patients. Clinical trial information: NCT03923166.