Background: Conventional anthracyclines are particularly active in HER2-positive breast cancer (BC), but their use concomitantly with anti-HER2 agents is limited by cardiotoxicity. Pegylated liposomal doxorubicin (PLD) and lapatinib (L) offer a safer alternative for combining these two classes of agents. Methods: This is an open label phase Ib study, with 3+3 dose escalation design. Patients with HER2-positive (FISH amplified or immunohistochemistry 3+) advanced BC, progressing after trastuzumab with a cumulative dose of doxorubicin ≤ 240 mg/m² or equivalent, received PLD 30 mg/m² intravenously on day 1 plus escalating doses of L orally on days 1-21 of each 21-day cycle (L dose levels 1 / 2: 1250 / 1500 mg/m²). The primary endpoint was to define the maximum tolerated dose (MTD) at first cycle, and secondary endpoints were the activity and safety profile with multiple cycles. Results: Nine patients out of 11 enrolled were evaluable (1 excluded for allergic reaction at first PLD dose, 1 withdrew consent): 3 at dose level 1 and 6 at level 2. Median age was 65 years (range 43-77), ECOG PS 0 or 1, median number of prior systemic therapies for advanced BC 2 (range 0-3). Median number of cycles were 7 for PLD (range 3-13), 6 for L (range 3-26). No dose-limiting toxicities (DLTs) occurred at dose level 1, while a DLT (G3 diarrhea) occurred at dose level 2, leading to the expansion of this cohort to 6 patients, with no further DLTs. Main grade 1-2 toxicities at first cycle were diarrhea (5 patients), mucositis (2), liver toxicity (2), nausea (1) and anorexia (1). Two episodes of G3 toxicity occurred at cycle 2 (colitis level 1, anorexia level 2) and 1 at cycle 3 (stomatitis + hand-foot syndrome level 2), leading to treatment interruption or dose reduction. No case of left ventricular systolic dysfunction occurred. Although a formal MTD was not reached, given the long-term intent of treatment, level 2 was considered as the recommended phase 2 dose. Best responses were: 1 partial response (PR), 1 stable disease (SD) and 1 disease progression (PD) at level 1; 2 PR, 1 SD and 3 PD at level 2. Conclusions: The combination of PLD and L is sufficiently well tolerated and shows potential activity in pretreated HER2-positive advanced BC patients. Clinical trial information: 2009-012996-82.