Background: Anti-HER2 agents combined with chemotherapy is the treatment strategy for treatment-naive HER2-positive relapsed or metastatic breast cancer. This pooled study was conducted to investigate the efficacy of pyrotinib plus capecitabine as first-line treatment in patients with HER2-positive relapsed or metastatic breast cancer. Methods: Data were derived from three randomized controlled trials. In the phase 2 (NCT02422199) and the PHOEBE phase 3 (NCT03080805) studies, patients were randomized to receive pyrotinib plus capecitabine or lapatinib plus capecitabine. In the PHENIX phase 3 (NCT02973737) study, patients were randomly assigned and given pyrotinib plus capecitabine or placebo plus capecitabine. Patients who had received neither anti-HER2 agents nor chemotherapy for the relapsed or metastatic disease were included in the analyses, and the pooled tumor response data (per blinded independent central review) were reported herein. Results: In the pooled analysis of all three studies, 145 patients received pyrotinib plus capecitabine. The median progression free survival (PFS) was 12.4 months (95% CI, 11.1 months to not reached). The objective response rate (ORR) reached 72.4% (95% CI, 64.4% to 79.5%). In the pooled analysis involving the phase 2 and PHOEBE phase 3, 84 patients were treated with pyrotinib plus capecitabine and 62 patients with lapatinib plus capecitabine. The PFS was significantly prolonged with pyrotinib plus capecitabine vs lapatinib plus capecitabine (median, 12.4 months [95% CI, 11.1 months to not reached] vs 8.2 months [95% CI, 5.5 to 9.7 months]; hazard ratio, 0.40 [95% CI, 0.25 to 0.66]; p = 0.0001). The ORR was 71.4% (95% CI, 60.5% to 80.8%) with pyrotinib plus capecitabine compared with 58.1% (95% CI, 44.8% to 70.5%) with lapatinib plus capecitabine. Conclusions: The pooled analysis demonstrated pyrotinib plus capecitabine was efficacious as first-line therapy in patients with HER2-positive relapsed or metastatic breast cancer, offering a potent treatment option for these patients.