The use of intravenous nitrogen-containing bisphosphonates (N-BPs) is associated with the appearance of an acute phase response (APR) in a proportion of the patients for reasons that are poorly understood. The APR was attributed to the indirect activation of δ T cells with the release of interferon- and tumor necrosis factor (TNF). Forty patients with postmenopausal or senile osteoporosis (age range = 53–91 years) never previously treated with intravenous (iv) bisphosphonate, received a single 5-mg zoledronic acid (ZOL) iv infusion over 15 minutes. White blood cells were counted and analyzed with an automated hematology analyzer (ADVIA 2120i Siemens, New York, USA) and by flow cytometer (BD FACSCanto, Becton Dickinson). The occurrence of APR was defined by the occurrence of fever (>37 °C) during the next 2 days. Forty-two percent of patients (17 of 40) receiving the infusion of ZOL experienced an APR. Compared with the others they were younger (69 ± 7 years versus 74 ± 8 years; p = 0.06), and both the proportion and absolute number of δ T cells were significant higher (p = 0.02 and p = 0.013, respectively). Nonsignificant differences were found between the two groups for white blood cells and for the other circulating lymphocyte subpopulations. Age was inversely correlated with circulating δ T cells (p = 0.003) but the difference between the two groups in circulating δ T cells persisted for age-adjusted values and vice versa. In conclusion, the results of this study indicate that the number of circulating δ T cells, together with age, are important determinant of the occurrence of APR after intravenous infusion of ZOL and possibly of any other N-BPs. © 2012 American Society for Bone and Mineral Research