Vγ9Vδ2 T cells exert potent cytotoxicity toward various tumor cells and adoptive transfer of Vγ9Vδ2 T cells is an attractive proposition for cell based immunotherapy. Vγ9Vδ2 T cells expanded in the presence of Zoledronate and IL-2 express CD16 (FcγRIII), which raises the possibility that Vγ9Vδ2 T cells could be used in conjunction with tumor targeting monoclonal antibody drugs to increase antitumor cytotoxicity by antibody dependent cellular cytotoxicity (ADCC). Cytotoxic activity against CD20-positive B lineage lymphoma or chronic lymphocytic leukemia (CLL) and HER2-positive breast cancer cells was assessed in the presence of rituximab and trastuzumab, respectively. Cytotoxicity of Vγ9Vδ2 T cells against CD20-positive targets was higher when used in combination with rituximab. Similarly, Vγ9Vδ2 T cells used in combination with trastuzumab resulted in greater cytotoxicity against HER2-positive cells in comparison with either agent alone and this effect was restricted to the CD16+Vγ9Vδ2 T cell population. Our results show that CD16+Vγ9Vδ2 T cells recognize monoclonal antibody coated tumor cells via CD16 and exert ADCC similar to that observed with NK cells, even when target cells are relatively resistant to monoclonal antibodies or Vγ9Vδ2 T cells alone. Combination therapy involving ex vivo expanded CD16+Vγ9Vδ2 T cells and monoclonal antibodies may enhance the clinical outcomes for patients treated with monoclonal antibody therapy. © 2008 Wiley-Liss, Inc.