e12604 Background: Neoadjuvant therapy plays an important role in improving the clinical efficacy for patients with stage II-III epidermal growth factor receptor 2 (HER2)-positive breast cancer. Pyrotinib, a new irreversible tyrosine kinase inhibitor (TKI), combined with capecitabine have demonstrated a promising anti-tumour activity in metastatic breast cancer. Here, we conducted a multicenter, randomized, phase II, open-label trial aiming exploring the outcomes of adding pyrotinib to EC-TH neoadjuvant therapy. Methods: Patients aged 18–65 years old with invasive carcinoma, cT1-4N0-3M0 stage, HER2-positive breast cancer were enrolled. Cases were randomly assigned into neoadjuvant therapy with four cycles of epirubicin and cyclophosphamide followed by four cycles of docetaxel (or Paclitaxel for Injection, albumin bound) and trastuzumab (EC-TH), or pyrotinib (400mg day 1-21) combined with EC-TH. Results: 56 patients had completed 8 cycles of neoadjuvant therapy (40 in the treatment group and 16 in the controlled group). 20 patients underwent radical surgery after neoadjuvant therapy. Compared with EC-TH along (37.5%, 3/8), the addition of pyrotinib to EC-TH neoadjuvant chemotherapy (py+EC-TH) significantly increased the pathological complete response (pCR)rate (75%, 9/12) in patients with HER2-positive breast cancer. The objective response rate (ORR) was 87.5% (7/8) vs 100% (12/12) . The most common adverse effects (AEs) in the treatment group was diarrhoea with grade 3 occurred in 3 cases (7.5% 3/40), which most limited in the first treatment cycle. No grade 3 diarrhoea was observed in controlled group. Other AEs including leukopenia occurred similarly in both groups and no cardiovascular dysfunction was observed. Conclusions: Pyrotinib added to EC-TH neoadjuvant therapy significantly increased the pCR rate, suggesting an applicable strategy for HER2-positive breast cancer. Clinical trial information: NCT04290793.