Copyright © 2016 the Author(s). Published by Wolters Kluwer Health, Inc. All rights reserved. Introduction: CD3+ gd+ T cells comprise 2% to 5% of circulating T cells with Vg9Vd2+ cells the dominant circulating subtype. Vg9Vd2+ cells recognize non-peptide phosphoantigens and stress-associated NKG2D ligands expressed on malignant cells. Strategies that incorporate the tumoricidal properties of gd T cells represent a promising immunotherapeutic strategy for treatment of solid malignancies including neuroblastoma (NB). In this prospective, non-randomized Phase I trial, we assessed whether circulating Vg9Vd2+ cells could be safely expanded using intravenous ZOL (Zoledronate [Zometa®]) and subcutaneous Interleukin-2 (IL-2) in patients with refractory NB. Methods: Patients 2 to 21 years of age with refractory neuroblastoma with no known curative therapeutic options received ZOL on day 1, and IL-2 on days 1 to 5 and 15 to 19 of each 28-day cycle (n=4). Lymphocyte immunophenotyping was assessed weekly. Immunophenotyping studies from the treatment group were compared with healthy pediatric controls (n=16; range, 5y-15y) and of untreated NB disease controls (n=9; range, 4m-18y). Results: Treatment was well tolerated with no unexpected grade 3 and 4 toxicities. Lymphocyte subset counts did not differ significantly between volunteers and disease controls with the exception of gd+ T cell counts that were significantly higher in healthy volunteers (212+93 vs. 89+42, P=0.05). Study patients showed increases in circulating gd+ T cell count (3-10 fold) after the first week, increasing into the range seen in healthy volunteers (125+37, P=0.1940). Interestingly, all ZOL+IL-2 treated patients showed significant increases in CD3+CD4+CD27hiCD127dim T cells that rose weekly in 2 patients throughout the 4 weeks of observation (maximum 41% and 24% of total CD3+CD4+ T cells, respectively). Conclusions: In summary, combined ZOL and IL-2 is well tolerated and restored gd+ T cell counts to the normal range with a moderate expansion of Natural Killer cells. Progressive increases in circulating CD4+ T cells with a regulatory phenotype cells may offset beneficial effects of this therapy.