To study the impact of anti-HER2 therapy and response of primary tumor on distant disease free survival (DDFS) of the patients with HER2-positive breast cancer.The clinical data of the patients with HER2-positive breast cancer treated with neoadjuvant systemic therapy were analyzed retrospectively.Patients treated with preoperative anti-HER2 therapy and chemotherapy had a significant improved pathological complete response (pCR) rate (48.4%) compared with those treated with preoperative chemotherapy (17.2%) (P=0.000). The median follow-up period was 62(6-160) months. The 5-year DDFS in patients with anti-HER2 therapy and patients without anti-HER2 therapy was 93.5% and 83.3% respectively (P=0.006). The 5-year DDFS in patients achieving a pCR and patients not achieving a pCR was 94.7% and 82.6% respectively(P=0.001). Among patients achieving a pCR, anti-HER2 therapy did not improve DDFS significantly (P=0.960). Benefits of anti-HER2 therapy in DDFS among patients without a pCR achieved statistical significance (P=0.028).Combination of neoadjuvant anti-HER2 therapy and chemotherapy resulted in a higher pCR rate in HER2-overexpressing primary breast cancer. Patients treated with neoadjuvant systemic therapy who achieved a pCR have excellent outcome regardless of whether they received anti-HER2 therapy.