Background: The combination of docetaxel, carboplatin, and trastuzumab (TCH) is a standard adjuvant and neoadjuvant regimen for patients (pts) with HER2-positive breast cancer. Ixabepilone is a microtubule stabilizer active in taxane-refractory metastatic breast cancer (MBC) and in the neoadjuvant setting, where ixabepilone monotherapy yielded a pathologic complete response rate (pCR) of 18%. In HER2 + MBC, weekly ixabepilone with carboplatin plus trastuzumab yielded a 44% response rate. We evaluated ixabepilone in lieu of docetaxel in the TCH regimen as neoadjuvant treatment in HER2+ breast cancer. Methods: Eligibility criteria: locally advanced (clinical T1-T3, N0-N2, M0) breast adenocarcinoma, HER2+ (IHC3+ or FISH > 2), ECOG PS ≤2, and normal LVEF. Pts received ixabepilone 40 mg/m², carboplatin AUC=6, and trastuzumab 6mg/kg (8mg/kg loading dose) IV on day 1 q21 days x 6 cycles. Tumor assessments were performed after 3&6 cycles. Definitive surgery and trastuzumab to complete a 12-month course followed. Radiation and/or antiestrogen therapy was prescribed per institutional guidelines. pCR (no residual invasive cancer in breast or lymph nodes) was the primary endpoint. Results: 41 women (median tumor size 2.8 cm, ER-/PR- 54%) were treated from 4/09 – 4/10. 83% completed 6 cycles of neoadjuvant treatment. 7 pts did not complete 6 cycles, 5 due to toxicity (hematologic – 2 pts; nonhematologic – 3 pts) and 1 due to disease progression. One pt with a clinical CR went to surgery after 4 cycles. 36 pts had definitive surgery (mastectomy 64%, breast conservation 36%), 21 pts (58%) achieved pCR; 2 pts had CR at the primary site (with residual involved nodes). 1 pt progressed post surgery while receiving adjuvant trastuzumab. Grade 3/4 toxicities were primarily hematologic, including: neutropenia (80%), anemia (34%), thrombocytopenia (27%), neuropathy (12%), nausea/vomiting (17%), diarrhea (10%), and febrile neutropenia (5%). No cardiotoxicity occurred. Conclusions: The combination of ixabepilone, carboplatin, and trastuzumab as neoadjuvant therapy was well-tolerated with similar pCR rates to other neoadjuvant taxane/trastuzumab-containing combinations.