Background: Trastuzumab is the most widely used anti-HER2 agent in patients (pts) with HER2-positive breast cancer, both in (neo)adjuvant and metastatic settings; however, drug resistance is inevitable. This pooled study aimed to investigate the efficacy of pyrotinib plus capecitabine in pts with HER2-positive, trastuzumab-resistant relapsed or metastatic breast cancer. Methods: Data were derived from three randomized controlled trials, including a phase II (NCT02422199) and the PHOEBE phase III (NCT03080805) study comparing pyrotinib plus capecitabine vs lapatinib plus capecitabine and the PHENIX phase III (NCT02973737) study comparing pyrotinib plus capecitabine vs placebo plus capecitabine. Pts with trastuzumab-resistant disease were included in the analyses, including 39 pts who had relapsed within six months after adjuvant trastuzumab and 57 pts who had progressed within three months of trastuzumab treatment for metastatic disease. The pooled tumor response data (per blinded independent central review) were reported herein. Results: In the pooled analysis of all three studies, 63 pts received pyrotinib plus capecitabine. Among them, 28 (44.4%) pts had disease progression or died. The median progression free survival (PFS) was 12.4 months (95% CI, 6.9 to not reached). In total, 40 pts (63.5% [95% CI, 50.4% to 75.3%]) achieved objective response, and the estimated median duration of response (DoR) was 11.1 months (95% CI, 6.9 to not reached). In the pooled analysis involving the phase II and PHOEBE phase III, 43 pts were treated with pyrotinib plus capecitabine and 33 pts with lapatinib plus capecitabine. In total, 18 (41.9%) pts with pyrotinib plus capecitabine and 17 (51.5%) pts with lapatinib plus capecitabine had disease progression or died. The PFS tended to be prolonged with pyrotinib plus capecitabine vs lapatinib plus capecitabine (median, 12.4 months [95% CI, 6.9 to not reached] vs 6.9 months [95% CI, 5.5 to not reached]; hazard ratio, 0.62 [95% CI, 0.31 to 1.24]; p=0.0864). The objective response rate was 67.4% (95% CI, 51.5% to 80.9%) with pyrotinib plus capecitabine compared with 54.5% (95% CI, 36.4% to 71.9%) with lapatinib plus capecitabine. The estimated median DoR was 11.1 months [95% CI, 6.9 to not reached] vs not reached [95% CI, 4.2 months to not reached], respectively. Conclusions: Pyrotinib plus capecitabine showed favorable efficacy in pts with HER2-positive, trastuzumab-resistant relapsed or metastatic breast cancer. This combination could be a treatment option for this population.