Abstract Background : There is extensive preclinical evidence that bisphosphonates, especially zoledronic acid (ZOL), exhibit anti-tumor effects (inhibition of tumor cell adhesion, migration, invasion and proliferation, and induction of cell death). ZOL reduces tumor-associated angiogenesis and vascular endothelial growth factor (VEGF) production in different animal models of cancer. In the Adjuvant Treatment with Zoledronic Acid in Stage II/III Breast Cancer Study (AZURE), it was observed a reduction in residual invasive tumor size, ∼ 2-fold improved complete pathologic response rates, and lower mastectomy rates with chemotherapy plus ZOL versus chemotherapy alone. The current hypothesis is that adding ZOL to neoadjuvant chemotherapy will increase the efficacy of this neoadjuvant treatment, thanks to a direct anti-cancer activity of ZOL and/or a synergic anti-cancer effect with chemotherapy. The aim of this study was to evaluate the clinical, pathological and biological impact of adding ZOL to neoadjuvant chemotherapy in locally advanced breast cancer. Methods : A multicenter prospective phase II trial (NEOZOL) was performed in France to compare the effects of adding ZOL to neoadjuvant chemotherapy with that of neoadjuvant chemotherapy alone. Patients were randomized 1:1 to receive 4-mg ZOL monthly or no ZOL with chemotherapy cycles. Patient's eligibility criteria were women 18 years of age or older with absence of contraindication to treatment with ZOL and breast cancer (TNM IIa, IIb, IIIa) larger than 2cm in maximal diameter able to benefit from neoadjuvant chemotherapy. The primary end point was circulating concentrations of VEGF. The secondary end points were clinical, radiological, pathological and biological tumor response rates, and the breast conservation rate. The planned sample size was 38 patients per arm with a power of 95,4 %. The protocol has been funded by Novartis and was reviewed by an Ethical Committee (CPP Lyon IV). This study is registered in the NCI database. Results: due to low accrual, the study was stopped after inclusion of 71 patients between May 2010 and July 2013. 53 patients were randomized and 3 patients were excluded after randomization due to deviation to the protocol. Of the remaining 50 patients, 24 were randomized in arm A (ZOL treatment) and 26 in arm B (control arm). Baseline clinicopathologic characteristics were well balanced. .No side effect related to ZOL treatment was reported. Circulating VEGF levels did not statistically significantly differ between both arms. Regarding secondary end-points, there was a trend towards a more conservative surgery in arm A, compared with arm B. Conclusion : adding ZOL to neoadjuvant chemotherapy in locally advanced breast cancer may increase the efficiency of chemotherapy, improving surgical treatment. Citation Format: Mathevet P, Magaud L, Clézardin P. Adding zoledronic acid to neo-adjuvant chemotherapy may improve the efficiency of chemotherapy in locally advanced breast cancer: Results from the prospective randomized study NEOZOL. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P6-13-19.