The purpose of this trial was to determine cardiac toxicity and overall efficacy of the pegylated liposome doxorubicin (PLD)-docetaxel couplet alone if HER2-negative metastatic breast cancer (internal control) or with trastuzumab if HER2-positive disease. Upon central HER2 confirmation, 84 eligible patients received induction with PLD (30 mg/m(2)) and docetaxel (60 mg/m(2)) every 3 weeks (maximum eight cycles), alone if HER2-negative (arm A; N = 38) or plus trastuzumab (4 mg/kg once, then 2 mg/kg weekly) if HER2-positive disease (arm B; N = 46) as first-line therapy. Maintenance therapy (without PLD) allowed. Primary objectives were to determine whether congestive heart failure (CHF) rate >3% and the efficacy/toxicity of each arm. CHF rate was <3% in each arm. Response rate, median progression-free-, and overall survival in arms A and B were 47.4 and 45.7%, 11 and 10.6 months, and 24.6 and 31.8 months, respectively. Trastuzumab arm was associated with higher rates of hand foot syndrome (grade 3: 22 vs. 38%; P = 0.16; overall 51 vs. 75%, P = 0.03) and treatment discontinuation due to toxicity/patient withdrawal (13 vs. 28%; P = 0.11). Febrile neutropenia occurred in approximately 10% of patients. In conclusion, concurrent administration of trastuzumab with PLD-docetaxel was not associated with higher risk of cardiac toxicity compared with PLD-docetaxel alone, but led to excessive hand-foot syndrome.