This prospective, parallel-group, dose-escalation study evaluated the cardiac safety of trastuzumab (Herceptin) plus epirubicin/cyclophosphamide (EC) in women with human epidermal growth factor receptor-2 (HER2)-positive metastatic breast cancer (MBC) and determined an epirubicin dose for further evaluation. HER2-positive patients received standard-dose trastuzumab plus epirubicin (60 or 90 mg/m(2))/cyclophosphamide (600 mg/m(2)) 3-weekly (EC60+H, n=26; EC90+H, n=25), for four to six cycles; 23 HER2-negative patients received EC alone (90/600 mg/m(2)) 3-weekly for six cycles (EC90). All patients underwent thorough cardiac evaluation. Two EC90+H-treated patients experienced symptomatic congestive heart failure 4.5 and 6 months after the end of chemotherapy. One EC60+H-treated patient experienced an asymptomatic decrease in left ventricular ejection fraction (LVEF) to <50% 6 months after the end of chemotherapy. No such events occurred in control patients. Asymptomatic LVEF decreases of >10% points were detected in 12 (48%), 14 (56%) and 5 (24%) patients treated with EC60+H, EC90+H, and EC90. Objective response rates with EC60+H and EC90+H were >60%, and 26% for EC90 alone. These results indicate that trastuzumab may be combined with EC with manageable cardiotoxicity and promising efficacy.