The combination therapy of doxorubicin and trastuzumab has been proven to be highly effective for metastatic breast cancer (MBC) patients with Her2/neu over-expressing tumors. However, this regimen is characterized by frequent cardiac toxicity, occurring in 27% of all treated patients and aggravating when the two substances are given concurrently. Pegylated liposomal doxorubicin (PLD) as a single agent reduces significantly cardiac toxicity and maintains efficacy compared to conventional doxorubicin. This prospective open labeled, multicenter phase II study assessed the potential cardiotoxicity and efficacy of PLD and trastuzumab as first and second line combination therapy in Her2/neu over-expressing MBC patients. Patients with Her2 over-expressing, measurable MBC with a baseline left ventricular ejection fraction (LVEF) > or =50% were treated with PLD 40 mg/m(2) every 4 weeks for 6 up to 9 cycles and weekly trastuzumab (4 mg/kg loading dose, then 2 mg/kg). Cardiotoxicity was defined as the appearance of clinical signs or symptoms of congestive heart failure in combination with a decrease in LVEF < or =44% or > or =10 units below the normal value of 50% in the obligatory, subsequently performed transthoracic echocardiography. Due to conflicting interests, the planned accrual goal of 30 patients was not reached. Finally 16 patients were enrolled. Ten patients presented with more than one metastatic site and six of them were in second-line therapy. The median LVEF in the study cohort was 66.1 +/- 8.68% at baseline, 62.7 +/- 5.11% after 6 cycles of therapy, 64.4 +/- 7.61% at the first follow up and did not change significantly (61.0 +/- 5.56% even at the 5th follow-up). Six out of 12 assessable patients (50.0%) demonstrated a clinical benefit and after a median follow-up of 15.4 months a median progression free survival of 9.67 and a median overall survival of 16.23 months. Non-cardiac side effects were mild with only 3 CTC grade 3 events of 247 treatment cycles (1.2%) and no grade 4 toxicities. The combination of PLD and trastuzumab in patients with Her2/neu over-expressing metastatic breast cancer is a safe, feasible and effective therapy. However, cardiac function should be monitored at close intervals. Due to the promising clinical response rates and mild toxicity profile in this prognostically unfavorable group, this combination therapy should be evaluated in larger studies.