BACKGROUND: Although the efficacy of zoledronic acid in postmenopausal women with breast cancer has been suggested, the underlying mechanism has not been fully clarified. Therefore, which patients may benefit from zoledronic acid and the optimal frequency of zoledronic acid administration are unclear. This study evaluates the effects of zoledronic acid on the tumor response in postmenopausal women with breast cancer and explores the relationship between its efficacy and γδ T cells. METHODS/DESIGN: This study is an open-label, multi-institutional, single-arm, phase II clinical trial. Zoledronic acid will be administered once during preoperative hormonal therapy with letrozole for 24 weeks in postmenopausal women with Estrogen Receptor (ER)-positive , Human Epidermal Growth Factor Receptor 2 (HER2)-negative, clinical T1 or T2 N0M0 breast cancer. The primary endpoint is the objective response rate measured by MRI at 12 and 24 weeks. The secondary endpoints are the associations between the frequency of Vγ2Vδ2 T cells before the administration of zoledronic acid and the objective response, the association between the frequency of Vγ2Vδ2 T cells and the Preoperative Endocrine Prognostic Index score, and the association between the frequency of Vγ2Vδ2 T cells and Ki67 (MIB-1 index). DISCUSSION: This study is designed to determine the add-on effect of zoledronic acid during preoperative hormonal therapy and to investigate the changes of the frequency of Vγ2Vδ2 T cells after the administration of zoledronic acid to explore the potential mechanism of zoledronic acid in breast cancer patients. TRIAL REGISTRATION: This trial was registered at the UMIN Clinical Trials Registry as UMIN000008701.