This study aimed to determine the correlation of human epidermal growth factor receptor 2 (HER2) codon 655 A>G polymorphism with cardiotoxicity risk in HER2-positive breast cancer patients undergoing epirubicin/cyclophosphamide followed by docetaxel plus trastuzumab (EC-D-T) adjuvant chemotherapy. Peripheral blood from 91 HER2-positive breast cancer patients was collected for HER2 codon 655 A>G genotyping before initiation of EC-D-T adjuvant chemotherapy (M0). Left ventricular ejection fraction (LVEF), cardiac troponin I (cTnI), and N terminal pro B type natriuretic peptide (NT-proBNP) levels were measured at M0, M3, M6, M9, M12 and M15. Cardiotoxicity was assessed at each time point after initiation of adjuvant chemotherapy. There were 77 cumulative cardiotoxicity events, and totally 26 patients had cardiotoxicity with incidence of 28.6% during the study. LVEF was decreased, cTnI was increased but NT-proBNP was similar in cardiotoxicity patients compared to non-cardiotoxicity patients at each time point. Additionally, the prevalences of HER2 codon 655 AA, AG, GG genotypes were 70.3%, 26.4% and 3.3% respectively. LVEF was lower at each time point after initiation of adjuvant chemotherapy and incidence of cardiotoxicity was increased in patients with HER2 codon 655 AG/GG genotypes compared to those with HER2 codon 655 AA genotype. Logistic regression analysis further revealed that HER2 codon 655 A>G, smoking and baseline cTnI were independent predictive factors for increased cardiotoxicity risk. In conclusion, HER2 codon 655 A>G was an independent predictive factor for increased cardiotoxicity risk in HER2-positive breast cancer patients undergoing EC-D-T adjuvant chemotherapy. IJCEP Copyright © 2020.