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Amino-bisphosphonates are potent activators of human γδ T cells. The aim of our study was to evaluate the immunomodulating properties of a single-dose of zoledronic acid (ZA) on γδ T cells in a select group of disease-free breast cancer patients with osteopenia. Blood samples were obtained, from 23 patients, before and 7, 28, 56, 90 and 180 days after a single-dose (4 mg) of ZA and analyzed by flow cyometry. A significant decrease of the different γδ T cell subsets was observed: Naïve (CD3+/Vdelta2+/CD45RA+/CD27+) after 180 days ( P < 0.01); Central Memory (CD3+/Vdelta2+/CD45RA-CD27+) after 28 ( P < 0.05), 90 ( P < 0.01) and 180 days ( P < 0.01); and Effector Memory (CD3+/Vdelta2+/CD45RA-/CD27-) after 56 ( P < 0.01) and 90 ( P < 0.05) days. Based on the observed γδ T cells kinetics patients could be divided in two groups: “responders” that showed a significant decrease in total numbers of γδ T cells and “non-responders” that showed no significant change. However, in vitro phosphoantigen stimulation of patients cells did not show significant differences in terms of IFN-γ response by Vδ2 T cells. We describe for the first time a long-lasting activation of effector subsets of γδ T cells in disease-free breast cancer patients after a single-dose of ZA. Our results highlight the need to further investigate the clinical significance of the immunomodulating properties of N-BPs. [ABSTRACT FROM AUTHOR]