Based on previous results obtained with non-pegylated liposomal-encapsulated doxorubicin (TLC-D99) together with paclitaxel and trastuzumab in patients with human epidermal growth factor receptor 2 (HER2)-positive locally advanced or metastatic breast cancer (BC), a similar regimen was evaluated in the neoadjuvant setting in a prospectively selected series of consecutive patients with clinical stage II-III BC. Primary and secondary objectives included the rate of pathologic complete response (pCR), safety, and predictive factors of pCR. Patients received six cycles of TLC-D99 (50 mg/m(2) every 3 weeks), paclitaxel (80 mg/m(2) weekly) and trastuzumab (4 mg/kg initial dose and 2 mg/kg weekly). All patients underwent surgery after treatment. pCR was defined as the absence of invasive cancer cells in the breast and the axilla. Sixty-two patients with a median age of 46.6 years were analyzed. Stage IIIA was diagnosed in 43.5% of patients and 14.5% had inflammatory BC. Conservative surgery was performed in 46.8% of the patients and pCR was achieved in 63% (95% CI 50.5-75.5). Patients with estrogen receptor (ER)-negative tumors presented a significantly higher pCR rate than patients with ER-positive tumors (74.4 vs 43.5%; P = 0.028). Forty-five patients (72.6%) completed study treatment and 80.6% received at least five treatment cycles. No patients developed congestive heart failure and 14.5% of patients showed a ≥ 10 % decrease in the left ventricular ejection fraction. The triple combination therapy assessed is effective and safe, offering a high pCR rate in patients with HER2-positive BC.