Abstract Background Nanoparticle albumin-bound paclitaxel (nab-Paclitaxel) is an alternative to standard taxanes for breast cancer (BC) treatment. We evaluated nab-Paclitaxel efficacy as neoadjuvant treatment for early estrogen receptor-positive (ER+), human epidermal growth factor receptor 2-negative (HER2-) disease. Materials and Methods Women with ER+, HER2-, stage II–III BC were treated preoperatively with four cycles of weekly nab-Paclitaxel (150 mg/m2), 3 weeks on and 1 week off. We hypothesized that poor pathological response rate (residual cancer burden [RCB] III; Symmans criteria) would be ≤16%. Results Eighty-one patients with a median age of 47 years were treated; 64.2% were premenopausal, and 69% of tumors were stage II. Residual cancer burden III rate was 28.4% (95% confidence interval [CI]: 18.6%–38.2%), RCB 0+I (good response) rate was 24.7% (95% CI: 15.3%–34.1%) and RCB 0 (complete response) rate was 7.4% (95% CI: 1.7%–13.1%). Objective response rate by magnetic resonance imaging was 76.5% and rate of conversion to breast conserving surgery was 40.0%. The most frequent grade 3 and 4 toxicity was neutropenia (12.3% and 3.7% of patients, respectively), without any febrile neutropenia. Sensory neuropathy grade 2 and 3 were seen in 25.9% and 2.5% of patients, respectively. Tumor secreted protein, acidic, cysteine-rich (SPARC) overexpression was significantly associated with RCB 0 (odds ratio: 0.079; 95% CI: 0.009–0.689; p = .0216). Conclusion Despite failing to confirm an RCB III rate ≤16% in nab-Paclitaxel-treated patients, the RCB 0+I rate indicates a significant drug antitumor activity with low rates of grade 3–4 toxicity. Our exploratory biomarker analysis suggests a potential predictive role of complete response for SPARC. Confirmatory analyses are warranted, adapting dose and schedule to decrease peripheral neurotoxicity. (Trial registration: European Clinical Trials Database study number: 2011-004476-10; ClinicalTrials.gov: NCT01565499).