Background: Neo-Adjuvant chemotherapy (NAC) allows patients to undergo breast conserving surgery, treats micro metastatic disease and improves patient outcomes. Achieving a complete pathologic response to NACT has prognostic significance in HER2+ and triple negative breast cancer. Anthracyclines are commonly integrated to Neo-adjuvant regimens. Their use is limited by cardiac and hematologic toxicity. We proposed that weekly Carboplatin and Nab-Paclitaxel is a well-tolerated regimen and aim to demonstrate that this approach can be a selective anthracycline sparing regimen with comparable improvement in recurrence free survival (RFS) and pathologic complete response (pCR). Methods: We conducted a single institution, open label, prospective Phase II clinical trial for patients with non-metastatic breast cancer who were eligible to receive NACT. All Patients with stage I-III breast cancers were treated with weekly Nab-paclitaxel (90 mg/m2) and carboplatin (AUC 2) for 12 weeks. Patients with HER2+ breast cancer received trastuzumab (4 mg/kg induction, followed by 2 mg/kg/week) weekly for 12 weeks. Triple negative and HR + patients received bevacizumab (10 mg/kg) every other week for 5 doses. Results: We enrolled 125 patients from February 2008 to December 2015. 85 pts were HER2- and 42 pts were HER2+. The pCR rate was 17.6% (15 pts) in the HER2- cohort and 50% (21 pts) in the HER2+ cohort. In the subgroup analysis based on hormone receptor (HR) status, pts with HR- tumor had more favorable response with higher rate of pCR compared with pts with HR+ tumor. In the HER2- cohort, the total pCR rate was 34% in HR- tumors vs 8% in HR+ tumors, P = 0.0018. After a median follow up of 53 months, overall survival was 88.9% for pts who achieved pCR and 77.7% for those who did not. HR = 0.3664, CI = 0.06147 to 2.1843, P = 0.34.In the HER2+ cohort the pCR rate was 33% in pts with HR+ tumors vs 72% in pts with HR- tumor, P = 0.0137. After a median follow up of 53 months, overall survival was 100% for pts who achieved pCR vs 20% in those who did not. The relapse-free survival was 90% vs 25% respectively (HR = 0.0669, CI = 0.00454 to 0.9251 P = 0.0016). In the entire study population, 6 pts (4.7%) had treatment discontinuation and 12 pts (9.4%) had dose reduction due to side effects. The rate of treatment disruption was higher in the HER2- cohort. Nausea, vomiting, and neutropenia were the most common side effects in both cohorts (7.9%) followed by thrombocytopenia and anemia (4.7%). Hematologic toxicity was the most common toxicity grade 3 and 4. Conclusions: Combination of nab-paclitaxel and carboplatin plus targeted therapy as an anthracycline sparing neoadjuvant chemotherapy showed a good pCR rate in HER2+ subgroup and moderate activity in TNBC subset. High rate of pCR was associated with high survival outcomes in HER2+ cohort. The regimen was well tolerated among both cohorts. Clinical trial information: NCT00618657.